The present invention relates to amine derivative compounds or their pharmacologically acceptable salts having superior insulin tolerance ameliorating effects, blood sugar lowering effects, anti-inflammatory effects, immunoregulatory effects, aldose reductase inhibitory effects, 5-lipoxygenase inhibitory effects, lipid peroxide formation inhibitory effects, PPAR activation effects, anti-osteoporosis effects, leukotriene antagonistic effects, fat cell promotion effects, cancer cell proliferation inhibitory effects and calcium antagonistic effects.
Moreover, the present invention relates to a preventing and/or therapeutic agent containing as an active ingredient the above-mentioned amine derivative compounds or their pharmacologically acceptable salts for diseases such as diabetes, hyperlipemia, obesity, glucose intolerance, hypertension, fatty liver, diabetic complications (including retinopathy, nephropathy, neuropathy, cataracts and coronary diseases), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (such as ischemic heart disease), cell injury induced by atherosclerosis or ischemic heart disease (such as brain injury induced by apoplexy), gout, inflammatory diseases (including arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis), cancer, osteoporosis and cataracts.
Moreover, the present invention relates to pharmaceutical compositions comprising a combination of the above amine derivative compounds or their pharmacologically acceptable salts and at least one kind of RXR activator, sulfonylurea agent, xcex1-glucosidase inhibitory agent, aldose reductase inhibitory agent, biguanide agent, statin compound, squalene synthesis inhibitory agent, fibrate compound, LDL disassimilation promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitory agent, antitumor agent and FBPase inhibitory agent (and particularly preferably antitumor agents and preventing and/or therapeutic agents for diabetes or diabetic complications).
At present, thiazolidine compounds, oxazolidine compounds and the like are reported to be useful as preventing or therapeutic agents for various diseases such as diabetes and hyperlipemia.
For example, oxazolidinedione derivatives having blood sugar and blood lipid lowering effects are disclosed in (1) Japanese Patent Application (Kokai) No. Hei 7-101945 and (2) Japanese Patent Application (Kokai) No. Hei 7-165735. However, the compounds of the inventions as claimed in these publications have a structure that differs from the structure of the compounds of the present invention in that the oxazolidinedione has a comparatively long chain aliphatic hydrocarbon group (the compounds of the present invention have a thiazolidinedione- or oxazolidinedione-methyl group), and although it may have a benzimidazole or imidazopyridine group, each group only has comparatively small substituents such as hydrocarbon groups (the compounds of the present invention are required to have a benzimidazole or imidazopyridine structure, and its substituent is comparatively large and must include an amino group and an aryl group).
In addition, an azolidinedione derivative having anti-diabetes effects is disclosed in (3) U.S. Pat. No. 5,985,884. However, the compound of the invention as claimed in this publication also has a different structure from the compounds of the present invention in that it is unable to have a benzimidazole or imidazopyridine structure having an amino group as its substituent.
Moreover, a thiazolidinedione compound capable of satisfactorily controlling blood sugar values is disclosed in (4) Japanese Patent Application (Kokai) No. Hei 5-213913. However, the compound of the invention as claimed in this publication also has a different structure from the compounds of the present invention in that it also requires a piperidine structure in the case of having a benzimidazole structure, and in that its substituent is comparatively small.
As a result of extensive studies on the synthesis of a series of amine derivative compounds and their pharmacological activity over the course of many years, the inventors of the present invention have found that amine derivative compounds having a novel structure have superior insulin tolerance ameliorating effects, blood sugar lowering effects, anti-inflammatory effects, immunoregulatory effects, aldose reductase inhibitory effects, 5-lipoxygenase inhibitory effects, lipid peroxide formation inhibitory effects, PPAR activation effects, anti-osteoporosis effects, leukotriene antagonistic effects, fat cell promotion effects, cancer cell proliferation inhibitory effects and calcium antagonistic effects, have less side effects, and have a high degree of antitumor activity, thereby leading to completion of the present invention.
It is another object of the present invention to provide a preventing and/or therapeutic agent containing as an active ingredient the above-mentioned amine derivative compounds or their pharmacologically acceptable salts for diseases such as diabetes, hyperlipemia, obesity, glucose intolerance, hypertension, fatty liver, diabetic complications (including retinopathy, nephropathy, neuropathy, cataracts and coronary diseases), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (such as ischemic heart disease), cell injury induced by atherosclerosis or ischemic heart disease (such as brain injury induced by apoplexy), gout, inflammatory diseases (including arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis), cancer, osteoporosis and cataracts.
Further, it is another object of the present invention to provide pharmaceutical compositions comprising a combination of the above amine derivative compounds or their pharmacologically acceptable salts and at least one kind of RXR activator, sulfonylurea agent, xcex1-glucosidase inhibitory agent, aldose reductase inhibitory agent, biguanide agent, statin compound, squalene synthesis inhibitory agent, fibrate compound, LDL disassimilation promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitory agent, antitumor agent and FBPase inhibitory agent (and particularly preferably antitumor agents and agents for treating and/or preventing diabetes or diabetic complications).
The present invention relates to an amine derivative compound of the formula (I): 
wherein:
R1 represents a carbamoyl group (which may have one or two substituents xcex1 described later), a thiocarbamoyl group (which may have one or two substituents xcex1 described later), a sulfonyl group (which has one substituent xcex1 described later) or a carbonyl group (which has one substituent xcex1 described later);
R2 and R3 are the same or different and each represent a hydrogen atom, a C1-C10 alkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex2 described later) or a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex2 described later on the aryl portion);
W1, W2 and W3 are the same or different and each represent a single bond or a C1-C8 alkylene group;
X, Y and Q each represent an oxygen atom or a sulfur atom;
Z represents a xe2x95x90CHxe2x80x94 group or a nitrogen atom;
Ar represents a benzene ring or a naphthalene ring;
L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom, a C1-C6 alkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex2 described later) or a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex2 described later on the aryl portion);
the substituent xcex1 represents (i) a C1-C10 alkyl group, (ii) a C1-C6 halogenoalkyl group, (iii) a C3-C10 cycloalkyl group, (iv) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3 described later), (v) a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex3 described later on the aryl portion), (vi) a C4-C11 cycloalkylcarbonyl group, (vii) a C7-C11 arylcarbonyl group (which may have from 1 to 3 substituents xcex3 described later on the aryl portion), (viii) a C8-C17 aralkylcarbonyl group (which may have from 1 to 3 substituents xcex3 described later on the aryl portion), (ix) an aromatic heterocyclic group (which may have from 1 to 3 substituents xcex3 described later), (x) an aromatic heterocyclic carbonyl group (which may have from 1 to 3 substituents xcex3 described later), (xi) a C1-C6 alkylsulfonyl group, (xii) a C1-C6 halogenoalkylsulfonyl group, (xiii) a C6-C10 arylsulfonyl group (which may have from 1 to 3 substituents xcex3 described later on the aryl portion), or (xiv) a C7-C16 aralkylsulfonyl group (which may have from 1 to 3 substituents xcex3 described later on the aryl portion);
the substituent, represents (i) a C1-C6 alkyl group, (ii) a C1-C6 halogenoalkyl group, (iii) a C1-C6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex4 described later), (vii) a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex4 described later on the aryl portion), (viii) a cyano group, (ix) a nitro group, or (x) an amino group (which may have one or two substituents xcex4 described later);
the substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a C1-C6 halogenoalkyl group, (iii) a C1-C6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a C3-C10 cycloalkyl group, (ix) a C6-C10 aryl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents), (x) a C7-C16 aralkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents on the aryl portion), (xi) a C1-C7 aliphatic acyl group, (xii) a C1-C7 aliphatic acyloxy group, (xiii) an amino group, (xiv) a di-(C1-C6 alkyl) amino group or (xv) a C1-C4 alkylenedioxy group;
the substituent xcex4 represents (i) a C1-C10 alkyl group, (ii) a C6-C10 aryl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents), (iii) a C7-C16 aralkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents on the aryl portion), (iv) a C1-C7 aliphatic acyl group, (v) a C4-C11 cycloalkylcarbonyl group, (vi) a C7-C11 arylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents), (vii) a C8-C17 aralkylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents on the aryl portion), (viii) an aromatic heterocyclic carbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents);
or a pharmacologically acceptable salt thereof.
In the present specification,
The xe2x80x9ccarbamoyl groupxe2x80x9d means an H2N(Cxe2x95x90O)xe2x80x94 group and in the case where the group has one or two substituents, one or two hydrogen atoms on the nitrogen atom are substituted by the substituents.
The xe2x80x9cthiocarbamoyl groupxe2x80x9d means an H2N(Cxe2x95x90S)xe2x80x94 group and in the case where the group has one or two substituents, one or two hydrogen atoms on the nitrogen atom are substituted by the substituents.
The xe2x80x9calkyl groupxe2x80x9d means a monovalent group formed by removing one hydrogen atom from a straight or branched chain aliphatic hydrocarbon.
The xe2x80x9caryl groupxe2x80x9d means a monovalent group formed by removing one hydrogen atom bonded to a ring of an aromatic hydrocarbon.
The xe2x80x9caralkyl groupxe2x80x9d means a monovalent group in which one hydrogen atom of the above alkyl group is substituted by the above aryl group.
The xe2x80x9calkylene groupxe2x80x9d means a divalent group generated by removing two hydrogen atoms from a carbon atom of a straight or branched chain aliphatic hydrocarbon.
The xe2x80x9chalogenoalkyl groupxe2x80x9d means a monovalent group in which one or more hydrogen atoms of the alkyl group described above are substituted by a halogen atom.
The xe2x80x9ccycloalkyl groupxe2x80x9d means a monovalent cyclic aliphatic hydrocarbon group which may be fused.
The xe2x80x9ccycloalkylcarbonyl groupxe2x80x9d means a monovalent group in which the above cycloalkyl group is substituted by a carbonyl group.
The xe2x80x9carylcarbonyl groupxe2x80x9d means a monovalent group in which the above aryl group is substituted by a carbonyl group.
The xe2x80x9caralkylcarbonyl groupxe2x80x9d means a monovalent group in which the above aralkyl group is substituted by a carbonyl group.
The xe2x80x9caromatic heterocyclic groupxe2x80x9d means a monocyclic or polycyclic heterocyclic group with an aromatic property having from 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
The xe2x80x9caromatic heterocyclic carbonyl groupxe2x80x9d means a monovalent group in which the above aromatic heterocyclic group is substituted by a carbonyl group.
The xe2x80x9calkylsulfonyl groupxe2x80x9d means a monovalent group in which the above alkyl group is substituted by a sulfonyl group.
The xe2x80x9carylsulfonyl groupxe2x80x9d means a monovalent group in which the above aryl group is substituted by a sulfonyl group.
The xe2x80x9caralkylsulfonyl groupxe2x80x9d means a monovalent group in which the above aralkyl group is substituted by a sulfonyl group.
The xe2x80x9calkoxy groupxe2x80x9d means a monovalent group generated by removing a hydrogen atom of a hydroxyl group from a straight or branched chain alcohol.
The xe2x80x9cdialkylamino groupxe2x80x9d means a monovalent group in which two alkyl groups described above, which are the same or different, are bonded to a nitrogen atom.
The xe2x80x9calkylenedioxy groupxe2x80x9d means a divalent group in which both ends of a straight or branched chain alkylene group are substituted by oxygen atoms.
The xe2x80x9caliphatic acyl groupxe2x80x9d means a monovalent group in which the above alkyl group is substituted by a carbonyl group.
The xe2x80x9caliphatic acyloxy groupxe2x80x9d means a monovalent group in which an oxygen atom is bonded to the carbonyl group of the aliphatic acyl group described above. xe2x80x9cCmxe2x80x94Cnxe2x80x9d means that a group has from m to n number of carbon atoms.
In the case where R2, R3 or substituent xcex1 or xcex4 represents a xe2x80x9cC1-C10 alkyl groupxe2x80x9d, xe2x80x9cC1-C10xe2x80x9d and xe2x80x9calkylxe2x80x9d have the same meanings as defined above. The group may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl or 7,7-dimethyloctyl. R2 and xcex1 are preferably a C1-C8 alkyl group, more preferably a C1-C6 alkyl group. R3 and xcex4 are preferably a C1-C8 alkyl group, more preferably a C1-C6 alkyl group, still more preferably a C1-C4 alkyl group, further more preferably a C1-C2 alkyl group, and most preferably a methyl group.
In the case where R2, R3 or L represents a xe2x80x9cC6-C10 aryl group (which may have from 1 to 3 substituents xcex2 described later)xe2x80x9d, in the case where substituent xcex1 represents xe2x80x9ca C6-C10 aryl group (which may have from 1 to 3 substituents xcex3 described later)xe2x80x9d and in the case where substituent xcex2 represents a xe2x80x9cC6-C10 aryl group (which may have from 1 to 3 substituents xcex4)xe2x80x9d, xe2x80x9cC6-C10xe2x80x9d and xe2x80x9carylxe2x80x9d have the same meanings as defined above and the expressions xe2x80x9cwhich may have from 1 to 3 substituents xcex2xe2x80x9d, xe2x80x9cwhich may have from 1 to 3 substituents xcex3xe2x80x9d and xe2x80x9cwhich may have from 1 to 3 substituents xcex4xe2x80x9d mean that the group has no substituent xcex2, xcex3 or xcex4 or that the group has from 1 to 3 substituents xcex2, xcex3 or xcex4 which are the same or different. The aryl portion may include phenyl, indenyl or naphthyl.
In the case where R2, R3 or L represents a xe2x80x9cC7-C16 aralkyl group (which may have from 1 to 3 substituents xcex2 described later on the aryl portion)xe2x80x9d, in the case where substituent xcex1 represents a xe2x80x9cC7-C16 aralkyl group (which may have from 1 to 3 substituent xcex3 described later on the aryl portion)xe2x80x9d and in the case where substituent xcex2 represents a xe2x80x9cC7-C16 aralkyl group (which may have from 1 to 3 substituents xcex4 on the aryl portion)xe2x80x9d, xe2x80x9cC7-C16xe2x80x9d, xe2x80x9caralkylxe2x80x9d and the expressions xe2x80x9cwhich may have from 1 to 3 substituents xcex2xe2x80x9d, xe2x80x9cwhich may have from 1 to 3 substituents xcex3xe2x80x9d and xe2x80x9cwhich may have from 1 to 3 substituents xcex4xe2x80x9d have the same meanings as defined above. The above aralkyl portion may include benzyl, naphthylmethyl, indenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl or 6-naphthylhexyl.
In the case where W1, W2 or W3 represents a xe2x80x9cC1-C8 alkylene groupxe2x80x9d, xe2x80x9cC1-C8 xe2x80x9d and xe2x80x9calkylenexe2x80x9d have the same meanings as defined above. The group may include methylene, methylmethylene, ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5-methylheptamethylene, 2-ethylhexamethylene, 2-ethyl-3-methylpentamethylene, or 3-ethyl-2-methylpentamethylene. It is preferably a straight chain C1-C6 alkylene group, more preferably a straight chain C1-C4 alkylene group, and still more preferably a straight chain C1-C2 alkylene group. With respect to W3, the methylene group is most preferred.
In the case where L or substituent xcex2 or xcex3 represents a xe2x80x9cC1-C6 alkyl groupxe2x80x9d, xe2x80x9cC1-C6xe2x80x9d and xe2x80x9calkylxe2x80x9d have the same meanings as defined above. The group may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpenthyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group. It is preferably a C1-C4 alkyl group, and more preferably a C1-C2 alkyl group.
In the case where substituent xcex1, xcex2 or xcex3 represents a xe2x80x9cC1-C6 halogenoalkyl groupxe2x80x9d, xe2x80x9cC1-C6xe2x80x9d and xe2x80x9chalogenoalkyl groupxe2x80x9d have the same meanings as defined above. The group may include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl. It is preferably a C1-C4 halogenoalkyl group, and more preferably a C1-C2 halogenoalkyl group.
In the case where substituent xcex1 or xcex3 represents a xe2x80x9cC3-C10 cycloalkyl groupxe2x80x9d, xe2x80x9cC3-C10xe2x80x9d and xe2x80x9ccycloalkyl groupxe2x80x9d have the same meanings as defined above. The group may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl or adamantyl. It is preferably a cyclopropyl, cyclohexyl or adamantyl group, and more preferably a cyclohexyl or adamantyl group.
In the case where substituent xcex1 or xcex4 represents a xe2x80x9cC4-C11 cycloalkylcarbonyl groupxe2x80x9d, xe2x80x9cC4-C11xe2x80x9d and xe2x80x9ccycloalkylcarbonyl groupxe2x80x9d have the same meanings as defined above. The group may include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, norbornylcarbonyl or adamantylcarbonyl, and is preferably C4-C7 cycloalkylcarbonyl.
In the case where substituent xcex1 represents a xe2x80x9cC7-C11 arylcarbonyl group (which may have from 1 to 3 substituents xcex3 to be described later on the aryl portion)xe2x80x9d, xe2x80x9cC7-C11xe2x80x9d, xe2x80x9carylcarbonyl groupxe2x80x9d and xe2x80x9cmay have from 1 to 3 substituents xcex3xe2x80x9d have the same meanings as defined above. The arylcarbonyl portion may include benzoyl, 1- or 2-indanecarbonyl, or 1- or 2-naphthoyl, and is preferably benzoyl.
In the case where substituent xcex1 represents xe2x80x9cC8-C17 aralkylcarbonyl group (which may have from 1 to 3 substituents xcex3 to be described later on the aryl portion)xe2x80x9d, xe2x80x9cC8-C17xe2x80x9d, xe2x80x9caralkylcarbonyl groupxe2x80x9d and xe2x80x9cmay have from 1 to 3 substituents xcex3xe2x80x9d have the same meanings as defined above. The aralkylcarbonyl portion may include phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, naphthylacetyl, 4-naphthylbutyryl or 6-naphthylhexanoyl, is preferably phenyl-C2-C7 alkylcarbonyl, and is more preferably phenyl-C2-C5 alkylcarbonyl.
In the case where substituent xcex1 represents an xe2x80x9caromatic heterocyclic group (which may have from 1 to 3 substituents xcex3 to be described later)xe2x80x9d, xe2x80x9caromatic heterocyclic groupxe2x80x9d and xe2x80x9cmay have from 1 to 3 substituents xcex3xe2x80x9d have the same meanings as defined above. The aromatic heterocyclic portion may include a 5-membered aromatic heterocyclic group such as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, or thiadiazolyl; a 6-membered aromatic heterocyclic group such as pyranyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl; or a 7-membered aromatic heterocyclic group such as azepinyl, preferably a 5- or 6-membered aromatic heterocyclic group.
In the case where substituent xcex1 represents an xe2x80x9caromatic heterocyclic carbonyl group (which may have from 1 to 3 substituents xcex3 to be described later)xe2x80x9d, xe2x80x9caromatic heterocyclic carbonyl groupxe2x80x9d and xe2x80x9cmay have from 1 to 3 substituents xcex3xe2x80x9d have the same meanings as defined above. The aromatic heterocyclic carbonyl portion may include a 5-membered aromatic heterocyclic carbonyl such as furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl, or thiadiazolylcarbonyl; a 6-membered aromatic heterocyclic carbonyl such as pyranylcarbonyl, nicotinoyl, isonicotinoyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, or pyrazinylcarbonyl; or a 7-membered aromatic heterocyclic carbonyl such as azepinylcarbonyl, and is preferably 5- or 6-membered aromatic heterocyclic carbonyl.
In the case where substituent xcex1 represents a xe2x80x9cC1-C6 alkylsulfonyl groupxe2x80x9d, xe2x80x9cC1-C6xe2x80x9d and xe2x80x9calkylsulfonyl groupxe2x80x9d have the same meanings as defined above. The alkylsulfonyl group may include methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, 1-ethylpropanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl, 3-methylpentansulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-imethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonyl, 2,3-dimethylbutanesulfonyl or 2-ethylbutanesulfonyl, is preferably a C1-C4 alkylsulfonyl group, more preferably a C1-C2 alkylsulfonyl group, and most preferably the methanesulfonyl group.
In the case where substituent xcex1 represents a xe2x80x9cC1-C6 halogenoalkylsulfonyl groupxe2x80x9d, xe2x80x9cC1-C6xe2x80x9d and xe2x80x9chalogenoalkylsulfonyl groupxe2x80x9d have the same meanings as defined above. The group may include trifluoromethanesulfonyl, trichloromethanesulfonyl, difluoromethanesulfonyl, dichloromethanesulfonyl, dibromomethanesulfonyl, fluoromethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, 2,2,2-trichloroethanesulfonyl, 2-bromoethanesulfonyl, 2-chloroethanesulfonyl, 2-fluoroethanesulfonyl, 2-iodoethanesulfonyl, 3-chloropropanesulfonyl, 4-fluorobutanesulfonyl, 6-iodohexanesulfonyl or 2,2-dibromoethanesulfonyl, is preferably a C1-C4 halogenoalkylsulfonyl group, more preferably a C1-C2 halogenoalkylsulfonyl group and most preferably trifluoromethanesulfonyl.
In the case where substituent xcex1 represents a xe2x80x9cC6-C10 arylsulfonyl group (which may have from 1 to 3 substituents xcex3 to be described later on the aryl portion)xe2x80x9d, xe2x80x9cC6-C10xe2x80x9d, xe2x80x9carylsulfonyl groupxe2x80x9d and xe2x80x9cmay have from 1 to 3 substituents xcex3xe2x80x9d have the same meanings as defined above. The arylsulfonyl portion may include phenylsulfonyl, indenylsulfonyl or naphthylsulfonyl, and is preferably phenylsulfonyl.
In the case where substituent xcex1 represents a xe2x80x9cC7-C16 aralkylsulfonyl group. (which may have from 1 to 3 substituents xcex3 to be described later on the aryl portion)xe2x80x9d, xe2x80x9cC7-C16xe2x80x9d, xe2x80x9caralkylsulfonyl groupxe2x80x9d and xe2x80x9cmay have, from 1 to 3 substituents xcex3xe2x80x9d have the same meanings as defined above. The aralkylsulfonyl portion includes benzylsulfonyl, naphthylmethylsulfonyl, indenylmethylsulfonyl, 1-phenethylsulfonyl, 2-phenethylsulfonyl, 1-naphthylethylsulfonyl, 2-naphthylethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl, 3-naphthylpropylsulfonyl, 1-phenylbutylsulfonyl, 2-phenylbutylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-naphthylbutylsulfonyl, 2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl, 5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl or 6-naphthylhexylsulfonyl, is preferably phenyl-C1-C6 alkylsulfonyl, and more preferably phenyl-C1-C4 alkylsulfonyl.
In the case where substituent xcex2 or xcex3 represents a xe2x80x9cC1-C6 alkoxy groupxe2x80x9d, xe2x80x9cC1-C6xe2x80x9dand xe2x80x9calkoxy groupxe2x80x9d have the same meanings as defined above. The group may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy, is preferably a C1-C4 alkoxy group, and more preferably a C1-C2 alkoxy group.
In the case where substituent xcex2 or xcex3 represents a xe2x80x9chalogen atomxe2x80x9d, it may include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom, chlorine atom or bromine atom, and more preferably a fluorine atom or chlorine atom.
In the case where substituent xcex3 or xcex4 represents a xe2x80x9cC6-C10 aryl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents)xe2x80x9d, the C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents include those described in the definition of each group described above. In addition to the nonsubstituted aryl group which is described as the aryl portion above, the group may include groups having substituents such as 4-methylphenyl, 4-methylnaphthyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 4-propylphenyl, 4-propylnaphthyl, 2-, 3-, or 4-(trifluoromethyl)phenyl, 2-, 3-, or 4-(trifluoromethyl)naphthyl, 3,4-bis(trifluoromethyl), 2,3,4-tris(trifluoromethyl)phenyl, 4-(tetrafluoropropyl)phenyl, 4-(tetrafluoropropyl)naphthyl, 4-methoxyphenyl, 4-methoxynaphthyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 4-propoxyphenyl, 4-propoxynaphthyl, 4-fluorophenyl, 4-fluoronaphthyl, 3,4-difluorophenyl or 2,3,4-trifluorophenyl, is preferably a phenyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents), more preferably a phenyl group (which may have one group selected from C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituent), and most preferably a phenyl group.
In the case where substituent xcex3 or xcex4 represents a C6-C10 aralkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents)xe2x80x9d, the C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents include those described in the definition of each group described above. In addition to the nonsubstituted aralkyl group which is described as the aralkyl portion above, the group may include groups having substituents such as 4-methylbenzyl, 2,3,4-trimethylbenzyl, 4-methylphenethyl, 2,3,4-trimethylphenethyl, 4-(4-methylphenyl)butyl, 2-, 3- or 4-(trifluoromethyl)benzyl, 3,4-bis(trifluoromethyl)benzyl, 2,3,4-tris(trifluoromethyl)benzyl, 4-(tetrafluoropropyl)benzyl, 4-(trifluoromethyl)phenethyl, 3,4-bis(trifluoromethyl)phenethyl, 2,3,4-tris(trifluoromethyl)phenethyl, 4-(tetrafluoropropyl)phenethyl, 4-[4-(trifluoromethyl)phenyl]butyl, 4-[4-(tetrafluoropropyl)phenyl]butyl, 6-[4-(trifluoromethyl)phenyl]hexyl, 6-[4-(tetrafluoropropyl)phenyl]hexyl, 2-, 3-, or 4-(trifluoromethyl)naphthylmethyl, 4-(tetrafluoropropyl)naphthylmethyl, 4-[4-(trifluoromethyl)naphthyl]butyl, 4-[4-(tetrafluoropropyl)naphthyl]butyl, 4-methoxybenzyl, 2,3,4-trimethoxybenzyl, 4-methoxyphenethyl, 2,3,4-trimethoxyphenethyl or 4-(4-methoxyphenyl)butyl, 4-fluorobenzyl, 2,3,4-trifluorobenzyl, 4-fluorophenethyl, 2,3,4-trifluorophenethyl or 4-(4-fluorophenyl)butyl, is preferably a phenyl-C1-C6 alkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents on the phenyl moiety), more preferably a phenyl-C1-C4 alkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents on the phenyl moiety), still more preferably a phenyl-C1-C2 alkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents on the phenyl moiety), further more preferably a phenyl-C1-C2 alkyl group (which may have one C1-C6 alkyl group, C1-C6 halogenoalkyl group, C1-C6 alkoxy groups or halogen atom as the substituent on the phenyl moiety), and most preferably a phenyl-C1-C2 alkyl group.
In the case where substituent xcex3 or xcex4 represents a xe2x80x9cC1-C7 aliphatic acyl groupxe2x80x9d, xe2x80x9cC1-C7xe2x80x9d and xe2x80x9caliphatic acyl groupxe2x80x9d have the same meanings as defined above. The group may include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl or crotonoyl, is preferably a C1-C5 aliphatic acyl group, more preferably a C1-C3 aliphatic acyl group, and most preferably acetyl.
In the case where substituent xcex3 represents a xe2x80x9cC1-C7 aliphatic acyloxy groupxe2x80x9d, xe2x80x9cC1-C7xe2x80x9d and xe2x80x9caliphatic acyloxy groupxe2x80x9d have the same meanings as defined above. The group may include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy or crotonoyloxy, is preferably a C1-C5 aliphatic acyloxy group, more preferably a C1-C3 aliphatic acyloxy group, and most preferably acetyloxy.
In the case where substituent xcex3 represents a xe2x80x9cdi-(C1-C6 alkyl)amino groupxe2x80x9d, xe2x80x9cC1-C6xe2x80x9d and xe2x80x9cdialkylamino groupxe2x80x9d have the same meanings as defined above. The group may include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino or N-ethyl-N-isopropylamino, is preferably a di-(C1-C4 alkyl)amino group and more preferably a di-(C1-C2 alkyl)amino group.
In the case where substituent xcex3 represents a xe2x80x9cC1-C4 alkylenedioxy groupxe2x80x9d, xe2x80x9cC1-C4xe2x80x9d and xe2x80x9calkylenedioxy groupxe2x80x9d have the same meanings as defined above. The group may include methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy or propylenedioxy, is preferably a C1-C3 alkylenedioxy group, and more preferably a C1-C2 alkylenedioxy group.
In the case where substituent xcex4 represents a xe2x80x9cC7-C11 arylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents)xe2x80x9d, the C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents include groups described in the definition of each group described above. In addition to the nonsubstituted C7-C11 aromatic acyl group which is described as the arylcarbonyl portion above, the group may include groups having substituents such as 4-methylbenzoyl, 4-methylnaphthoyl, 3,4-dimethylbenzoyl, 2,3,4-trimethylbenzoyl, 4-propylbenzoyl, 4-propylnaphthoyl, 2-, 3-, or 4-(trifluoromethyl)benzoyl, 2,3-, or 4-(trifluoromethyl)naphthoyl, 3,4-bis(trifluoromethyl)benzoyl, 2,3,4-tris(trifluoromethyl)benzoyl, 4-(tetrafluoropropyl)benzoyl, 4-(tetrafluoropropyl)naphthoyl, 4-methoxybenzoyl, 4-methoxynaphthoyl, 3,4-dimethoxybenzoyl, 2,3,4-trimethoxybenzoyl, 4-propoxybenzoyl, 4-propoxynaphthoyl, 4-fluorobenzoyl, 4-fluoronaphthoyl, 3,4-difluorobenzoyl, or 2,3,4-trifluorobenzoyl, is preferably a benzoyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents), and more preferably a benzoyl group (which may have one C1-C6 alkyl group, C1-C6 halogenoalkyl group, C1-C6 alkoxy groups or halogen atom as the substituent).
In the case where substituent xcex4 represents a xe2x80x9cC8-C17 aralkylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents on the aryl portion)xe2x80x9d, the C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents include groups described in the definition of each group described above. In addition to the nonsubstituted C8-C12 aromatic aliphatic acyl group which is described as the aralkylcarbonyl portion in the definition for substituent xcex1 above, the group may include groups having substituents such as 4-methylphenylacetyl, 4-(4-methylphenyl)butyryl, 6-(4-methylnaphthyl)hexanoyl, 2-, 3- or 4-(trifluoromethyl)phenylacetyl, 4-(tetrafluoropropyl)phenylacetyl, 4-[4-(trifluoromethyl)phenyl]butyryl, 6-[4-(trifluoromethyl)phenyl]hexanoyl, 4-(trifluoromethyl)naphthylacetyl, 6-[4(trifluoromethyl)naphthyl]hexanoyl, 4-methoxyphenylacetyl, 4-(4-methoxyphenyl)butyryl, 6-(4-methoxynaphthyl)hexanoyl, 4-fluorophenylacetyl, 4-(4-fluorophenyl)butyryl or 6-(4-fluoronaphthyl)hexanoyl, is preferably a phenyl-C2-C7 alkylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents on the aryl portion), and most preferably a phenyl-C2-C7 alkylcarbonyl group (which may have one C1-C6 alkyl group, C1-C6 halogenoalkyl group, C1-C6 alkoxy group or halogen atom as the substituent).
In the case where substituent xcex4 represents an xe2x80x9caromatic heterocyclic carbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents)xe2x80x9d, the C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents include groups described in the definition of each group described above. In addition to the heterocyclic carbonyl group having a nonsubstituted aromatic heterocyclic portion described as the aromatic heterocyclic carbonyl group in the definition for substituent xcex1 above, the groups having substituents may include methylfurylcarbonyl, methylthienylcarbonyl, methylpyrrolylcarbonyl, methylnicotinoyl, (trifluoromethyl)furylcarbonyl, (trifluoromethyl)thienylcarbonyl, (trifluoromethyl)pyrrolylcarbonyl, (trifluoromethyl)oxazolylcarbonyl, (trifluoromethyl)thiazolylcarbonyl, (trifluoromethyl)nicotinoyl, (tetrafluoropropyl)furylcarbonyl, (tetrafluoropropyl)thienylcarbonyl, (tetrafluoropropyl)pyrrolylcarbonyl, methoxyfurylcarbonyl, methoxythienylcarbonyl, methoxypyrrolylcarbonyl, methoxynicotinoyl, fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolylcarbonyl or fluoronicotinoyl, is preferably a 5- or 6-membered aromatic heterocyclic carbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms as the substituents), more preferably a 5- or 6-membered aromatic heterocyclic carbonyl group having one or two heteroatoms (which may be selected from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups and halogen atoms), and most preferably a 5- or 6-membered aromatic heterocyclic carbonyl group having one or two heteroatoms (which may have one C1-C6 alkyl group, C1-C6 halogenoalkyl group, C1-C6 alkoxy group or halogen atom as the substituent).
From the definition of the substituents xcex3 and xcex4 described above, in the case where substituent xcex1 represents a xe2x80x9cC6-C10 aryl group (which may have from 1 to 3 substituents xcex3 ),xe2x80x9d the groups having the substituents xcex3 may include 2-, 3- or 4-methylphenyl, dimethylphenyl, trimethylphenyl, 2-, 3- or 4-isopropylphenyl, 2,3-, 2,4- or 3,4-diisopropylphenyl, 2,4,6- or 3,4,5-triisopropylphenyl, 2-, 3- or 4-(trifluoromethyl)phenyl, bis(trifluoromethyl)phenyl, tris(trifluoromethyl)phenyl, methoxyphenyl, dimethoxyphenyl, 2-, 3- or 4-fluorophenyl, 2,3-, 2,4- or 3,4-difluorophenyl, 2,4,6- or 3,4,5-trifluorophenyl, 2-, 3- or 4-chlorophenyl, dichlorophenyl, trichlorophenyl, hydroxyphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-nitrophenyl, cyclopropylphenyl, cyclohexylphenyl, adamantylphenyl, biphenyl, (methylphenyl)phenyl, [(trifluoromethyl)phenyl]phenyl, (methoxyphenyl)phenyl, (fluorophenyl)phenyl, (chlorophenyl)phenyl, benzylphenyl, (methylbenzyl)phenyl, [(trifluoromethyl)benzyl]phenyl, (methoxybenzyl)phenyl, (fluorobenzyl)phenyl, (chlorobenzyl)phenyl, acetylphenyl, acetyloxyphenyl, aminophenyl, dimethylaminophenyl, diethylaminophenyl, 3,4- or 2,3-methylenedioxyphenyl, 3,4- or 2,3-ethylenedioxyphenyl, methylnaphthyl, dimethylnaphthyl, trimethylnaphthyl, isopropylnaphthyl, diisopropylnaphthyl, triisopropylnaphthyl, (trifluoromethyl)naphthyl, bis(trifluoromethyl)naphthyl, tris(trifluoromethyl)naphthyl, methoxynaphthyl, dimethoxynaphthyl, fluoronaphthyl, difluoronaphthyl, trifluoronaphthyl, chloronaphthyl, dichloronaphthyl, trichloronaphthyl, cyanonaphthyl, nitronaphthyl, cyclopropylnaphthyl, cyclohexylnaphthyl, adamantylnaphthyl, phenylnaphthyl, (methylphenyl)naphthyl, (trifluoromethylphenyl)naphthyl, (methoxyphenyl)naphthyl, (fluorophenyl)naphthyl, (chlorophenyl)naphthyl, benzylnaphthyl, (methylbenzyl)naphthyl, [(trifluoromethyl)benzyl]naphthyl, (methoxybenzyl)naphthyl, (fluorobenzyl)naphthyl, (chlorobenzyl)naphthyl, acetylnaphthyl, acetyloxynaphthyl, aminonaphthyl, dimethylaminonaphthyl, diethylaminonaphthyl, methylenedioxynaphthyl or ethylenedioxynaphthyl, is preferably a phenyl group (which may have 1 to 3 substituents xcex3), more preferably a phenyl group (which may have one or two substituents xcex3), and most preferably a phenyl group (which may have one substituent xcex3).
In the case where substituent xcex1 represents a xe2x80x9cC7-C16 aralkyl group (which may have from 1 to 3 substituents xcex3), the group having the substituents xcex3 may include methylbenzyl, dimethylbenzyl, trimethylbenzyl, isopropylbenzyl, diisopropylbenzyl, triisopropylbenzyl, 2-, 3- or 4-(trifluoromethyl)benzyl, bis(trifluoromethyl)benzyl, tris(trifluoromethyl)benzyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, hydroxybenzyl, cyanobenzyl, nitrobenzyl, cyclopropylbenzyl, cyclohexylbenzyl, adamantylbenzyl, phenylbenzyl, (methylphenyl)benzyl, [(trifluoromethyl)phenyl]benzyl, (methoxyphenyl)benzyl, (fluorophenyl)benzyl, (chlorophenyl)benzyl, benzylbenzyl, (methylbenzyl)benzyl, [(trifluoromethyl)benzyl]benzyl, (methoxybenzyl)benzyl, (fluorobenzyl)benzyl, (chlorobenzyl)benzyl, acetylbenzyl, acetyloxybenzyl, aminobenzyl, dimethylaminobenzyl, diethylaminobenzyl, methylenedioxybenzyl, ethylenedioxybenzyl, methylphenethyl, dimethylphenethyl, trimethylphenethyl, isopropylphenethyl, diisopropylphenethyl, triisopropylphenethyl, (trifluoromethyl)phenethyl, bis(trifluoromethyl)phenethyl, tris(trifluoromethyl)phenethyl, methoxyphenethyl, fluorophenethyl, difluorophenethyl, trifluorophenethyl, chlorophenethyl, hydroxyphenethyl, cyanophenethyl, nitrophenethyl, cyclopropylphenethyl, cyclohexylphenethyl, adamantylphenethyl, phenylphenethyl, benzylphenethyl, acetylphenethyl, acetyloxyphenethyl, aminophenethyl, dimethylaminophenethyl, diethylaminophenethyl, methylenedioxyphenethyl, ethylenedioxyphenethyl, methylnaphthylmethyl, dimethylnaphthylmethyl, trimethylnaphthylmethyl, isopropylnaphthylmethyl, diisopropylnaphthylmethyl, triisopropylnaphthylmethyl, (trifluoromethyl)naphthylmethyl, bis(trifluoromethyl)naphthylmethyl, tris(trifluoromethyl)naphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl, difluoronaphthylmethyl, trifluoronaphthylmethyl, chloronaphthylmethyl, hydroxynaphthylmethyl, cyanonaphthylmethyl, nitronaphthylmethyl, cyclopropylnaphthylmethyl, cyclohexylnaphthylmethyl, adamantylnaphthylmethyl, phenylnaphthylmethyl, benzylnaphthylmethyl, acetylnaphthylmethyl, acetyloxynaphthylmethyl, aminonaphthylmethyl, dimethylaminonaphthylmethyl, diethylaminonaphthylmethyl, methylenedioxynaphthylmethyl or ethylenedioxynaphthylnethyl, is preferably a phenyl-C1-C6 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), more preferably a phenyl-C1-C4 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), still more preferably a phenyl-C1-C2 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), and most preferably a phenyl-C1-C4 alkyl group (which may have one substituent xcex3 on the phenyl portion).
In the case where substituent xcex1 represents a xe2x80x9cC7-C11 arylcarbonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion)xe2x80x9d, the group having the substituents xcex3 may include methylbenzoyl, dimethylbenzoyl, trimethylbenzoyl, isopropylbenzoyl, diisopropylbenzoyl, triisopropylbenzoyl, (trifliuoromethyl)benzoyl, methoxybenzoyl, fluorobenzoyl, difluorobenzoyl, trifluorobenzoyl, chlorobenzoyl, dichlorobenzoyl, hydroxybenzoyl, cyanobenzoyl, nitrobenzoyl, acetylbenzoyl, acetyloxybenzoyl, aminobenzoyl, dimethylaminobenzoyl, methylenedioxybenzoyl, methylnaphthoyl, isopropylnaphthoyl, diisopropylnaphthoyl, triisopropylnaphthoyl, (trifluoromethyl)naphthoyl, methoxynaphthoyl, fluoronaphthoyl, difluoronaphthoyl, trifluoronaphthoyl, chloronaphthoyl, dichloronaphthoyl, hydroxynaphthoyl, cyanonaphthoyl, nitronaphthoyl, acetylnaphthoyl, acetyloxynaphthoyl, aminonaphthoyl, dimethylaminonaphthoyl or methylenedioxynaphthoyl, is preferably a benzoyl group (which may have from 1 to 3 substituents xcex3), more preferably a benzoyl group (which may have one or two substituents xcex3) and most preferably a benzoyl group (which may have one substituent xcex3).
In the case where substituent xcex1 represents the xe2x80x9cC8-C17 aralkylcarbonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion)xe2x80x9d, the group having the substituents xcex3 may include methylphenylacetyl, isopropylphenylacetyl, diisopropylphenylacetyl, triisopropylphenylacetyl, (trifluoromethyl)phenylacetyl, methoxyphenylacetyl, fluorophenylacetyl, difluorophenylacetyl, trifluorophenylacetyl, chlorophenylacetyl, dichlorophenylacetyl, hydroxyphenylacetyl, cyanophenylacetyl, nitrophenylacetyl, acetylphenylacetyl, acetyloxyphenylacetyl, aminophenylacetyl, dimethylaminophenylacetyl, methylenedioxyphenylacetyl, 4-(methylphenyl)butyryl, 4-(isopropylphenyl)butyryl, 4-(diisopropylphenyl)butyryl, 4-(triisopropylphenyl)butyryl, 4-[(trifluoromethyl)phenyl]butyryl, 4-(fluorophenyl)butyryl, 4-(difluorophenyl)butyryl, 4-(trifluorophenyl)butyryl, 4-(chlorophenyl)butyryl, 4-(hydroxyphenyl)butyryl, 4-(cyanophenyl)butyl, 4-(nitrophenyl)butyryl, 4-(acetylphenyl)butyryl, 4-(acetyloxyphenyl)butyryl, 4-(aminophenyl)butyryl, 4-(dimethylaminophenyl)butyryl or 4-(methylenedioxyphenyl)butyryl, is preferably a phenyl-C2-C7 alkylcarbonyl group (which may have from 1 to 3 substituents xcex3), more preferably a phenyl-C2-C5 alkylcarbonyl group (which may have from 1 to 3 substituents xcex3), and most preferably a phenyl-C2-C5 alkylcarbonyl group (which may have one substituent xcex3).
In the case where substituent xcex1 represents an xe2x80x9caromatic heterocyclic group (which may have from 1 to 3 substituents xcex3)xe2x80x9d, the group having the substituents xcex3 may include methylfuryl, isopropylfuryl, (trifluoromethyl)furyl, cyanofuryl, nitrofuryl, fluorofuryl, chlorofuryl, methylthienyl, isopropylthienyl, (trifluoromethyl)thienyl, cyanothienyl, nitrothienyl, fluorothienyl, chlorothienyl, methylpyrrolyl, isopropylpyrrolyl, (trifluoromethyl)pyrrolyl, cyanopyrrolyl, nitropyrrolyl, fluoropyrrolyl, chloropyrrolyl, methylpyridyl, isopropylpyridyl, (trifluoromethyl)pyridyl, cyanopyridyl, nitropyridyl, fluoropyridyl or chloropyridyl, is preferably a 5- or 6-membered aromatic heterocyclic group (which may have from 1 to 3 substituents xcex3), more preferably a 5- or 6-membered aromatic heterocyclic group (which may have one or two substituents xcex3), and most preferably a 5- or 6-membered aromatic heterocyclic group (which may have one substituent xcex3).
In the case where substituent xcex1 represents an xe2x80x9caromatic heterocyclic carbonyl group (which may have from 1 to 3 substituents xcex3)xe2x80x9d, the group having the substituents xcex3 may include methylfurylcarbonyl, isopropylfurylcarbonyl, (trifluoromethyl)furylcarbonyl, cyanofurylcarbonyl, nitrofurylcarbonyl, fluorofurylcarbonyl, chlorofurylcarbonyl, methylthienylcarbonyl, isopropylthienylcarbonyl, (trifluoromethyl)thienylcarbonyl, cyanothienylcarbonyl, nitrothienylcarbonyl, fluorothienylcarbonyl, chlorothienylcarbonyl, methylpyrrolylcarbonyl, isopropylpyrrolylcarbonyl, (trifluoromethyl)pyrrolylcarbonyl, cyanopyrrolylcarbonyl, nitropyrrolylcarbonyl, fluoropyrrolylcarbonyl, chloropyrrolylcarbonyl, methylnicotinoyl, isopropylnicotinoyl, (trifluoromethyl)nicotinoyl, cyanonicotinoyl, nitronicotinoyl, fluoronicotinoyl or chloronicotinoyl, is preferably a 5- or 6-membered aromatic heterocyclic carbonyl group (which may have from 1 to 3 substituents xcex3), more preferably a 5- or 6-membered aromatic heterocyclic carbonyl group (which may have one or two substituents xcex3), and most preferably a 5- or 6-membered aromatic heterocyclic carbonyl group (which may have one substituent xcex3).
In the case where substituent xcex1 represents a xe2x80x9cC6-C11 arylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion)xe2x80x9d, the group having the substituents xcex3 may include methylphenylsulfonyl, isopropylphenylsulfonyl, (trifluoromethyl)phenylsulfonyl, methoxyphenylsulfonyl, fluorophenylsulfonyl, chlorophenylsulfonyl, hydroxyphenylsulfonyl, cyanophenylsulfonyl, nitrophenylsulfonyl, cyclohexylphenylsulfonyl, adamantylphenylsulfonyl, biphenylsulfonyl, benzylphenylsulfonyl, acetylphenylsulfonyl, acetyloxyphenylsulfonyl, aminophenylsulfonyl, dimethylaminophenylsulfonyl, methylenedioxyphenylsulfonyl, methylnaphthylsulfonyl, dimethylnaphthylsulfonyl, trimethylnaphthylsulfonyl, isopropylnaphthylsulfonyl, (trifluoromethyl)naphthylsulfonyl, methoxynaphthylsulfonyl, fluoronaphthylsulfonyl, chloronaphthylsulfonyl, cyanonaphthylsulfonyl, nitronaphthylsulfonyl, cyclohexylnaphthylsulfonyl, adamantylnaphthylsulfonyl, phenylnaphthylsulfonyl, benzylnaphthylsulfonyl, acetylnaphthylsulfonyl, acetyloxynaphthylsulfonyl, aminonaphthylsulfonyl, dimethylaminonaphthylsulfonyl or methylenedioxynaphthylsulfonyl, is preferably a phenylsulfonyl group (which may have from 1 to 3 substituents xcex3), more preferably a phenylsulfonyl group (which may have one or two substituents xcex3), and most preferably a phenylsulfonyl group (which may have one substituent xcex3).
In the case where substituent xcex1 represents a xe2x80x9cC7-C16 aralkylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion)xe2x80x9d, the group having the substituents xcex3 may include methylbenzylsulfonyl, isopropylbenzylsulfonyl, (trifluoromethyl)benzylsulfonyl, methoxybenzylsulfonyl, fluorobenzylsulfonyl, chlorobenzylsulfonyl, hydroxybenzylsulfonyl, cyanobenzylsulfonyl, nitrobenzylsulfonyl, cyclohexylbenzylsulfonyl, adamantylbenzylsulfonyl, phenylbenzylsulfonyl, benzylbenzylsulfonyl, acetylbenzylsulfonyl, acetyloxybenzylsulfonyl, aminobenzylsulfonyl, dimethylaminobenzylsulfonyl, methylenedioxybenzylsulfonyl, methylphenethylsulfonyl, isopropylphenethylsulfonyl, (trifluoromethyl)phenethylsulfonyl, methoxyphenethylsulfonyl, fluorophenethylsulfonyl, chlorophenethylsulfonyl, hydroxyphenethylsulfonyl, cyanophenethylsulfonyl, nitrophenethylsulfonyl, cyclohexylphenethylsulfonyl, adamantylphenethylsulfonyl, phenylphenethylsulfonyl, benzylphenethylsulfonyl, acetylphenethylsulfonyl, acetyloxyphenethylsulfonyl, aminophenethylsulfonyl, dimethylaminophenethylsulfonyl, methylenedioxyphenethylsulfonyl, methylnaphthylmethylsulfonyl, isopropylnaphthylmethylsulfonyl, (trifluoromethyl)naphthylmethylsulfonyl, methoxynaphthylmethylsulfonyl, fluoronaphthylmethylsulfonyl, chloronaphthylmethylsulfonyl, hydroxynaphthylmethylsulfonyl, cyanonaphthylmethylsulfonyl, nitronaphthylmethylsulfonyl, cyclohexylnaphthylmethylsulfonyl, adamantylnaphthylmethylsulfonyl, phenylnaphthylmethylsulfonyl, benzylnaphthylmethylsulfonyl, acetylnaphthylmethylsulfonyl, acetyloxynaphthylmethylsulfonyl, aminonaphthylmethylsulfonyl, dimethylaminonaphthylmethylsulfonyl or methylenedioxynaphthylmethylsulfonyl, is preferably a phenyl-C1-C6 alkylsulfonyl group (which may have from 1 to 3 substituents xcex3), more preferably a phenyl-C1-C4 alkylsulfonyl group (which may have from 1 to 3 substituents xcex3), still more preferably a phenyl-C1-C2 alkylsulfonyl group (which may have from 1 to 3 substituents xcex3), and most preferably a phenyl-C1-C2 alkylsulfonyl group (which may have one substituent xcex3).
In the case where substituent xcex2 represents a xe2x80x9cC6-C10 aryl group (which may have from 1 to 3 substituents xcex4)xe2x80x9d, the group having the substituents xcex4 may include methylphenyl, isopropylphenyl, biphenyl, benzylphenyl, acetylphenyl, cyclohexylphenyl, adamantylphenyl, benzoylphenyl, phenylacetylphenyl, nicotinoylphenyl, methylnaphthyl, isopropylnaphthyl, phenylnaphthyl, benzylnaphthyl, acetylnaphthyl, cyclohexylnaphthyl, adamantylnaphthyl, benzoylnaphthyl, phenylacetylnaphthyl or nicotinoylnaphthyl, is preferably a phenyl group (which may have from 1 to 3 substituents xcex4), more preferably a phenyl group (which may have one or two substituents xcex4), and most preferably a phenyl group (which may have one substituent xcex4).
In the case where substituent xcex2 represents a xe2x80x9cC7-C16 aralkyl group (which may have from 1 to 3 substituents xcex4 on the aryl portion),xe2x80x9d the group having the substituents xcex4 may include methylbenzyl, isopropylbenzyl, phenylbenzyl, benzylbenzyl, acetylbenzyl, cyclohexylbenzyl, adamantylbenzyl, benzoylbenzyl, phenylacetylbenzyl, nicotinoylbenzyl, methylphenethyl, isopropylphenethyl, phenylphenethyl, benzylphenethyl, acetylphenethyl, cyclohexylphenethyl, adamantylphenethyl, benzoylphenethyl, phenylacetylphenethyl, nicotinoylphenethyl, methylnaphthylmethyl, isopropylnaphthylmethyl, phenylnaphthylmethyl, benzylnaphthylmethyl, acetylnaphthylmethyl, cyclohexylnaphthylmethyl, adamantylnaphthylmethyl, benzoylnaphthylmethyl, phenylacetylnaphthylmethyl or nicotinoylnaphthylmethyl, is preferably a phenyl-C1-C6 alkyl group (which may have from 1 to 3 substituents xcex4 on the phenyl portion), more preferably a phenyl-C1-C4 alkyl group (which may have from 1 to 3 substituents xcex4 on the phenyl portion), still more preferably a phenyl-C1-C2 alkyl group (which may have from 1 to 3 substituents xcex4 on the phenyl portion), and most preferably a phenyl-C1-C2 alkyl group (which may have one substituent xcex4 on the phenyl portion).
In the case where substituent xcex2 represents an xe2x80x9camino group which may have one or two substituents xcex4xe2x80x9d, the group may include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, phenylaamino, 1- or 2-indenylamino, 1- or 2-naphthylamino, benzylamino, 1- or 2-naphthylmethylanio, 1-indenylmethylamino, 1- or 2-phenethylamino, 1-, 2- or 3-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 6-phenylhexylamino, dibenzylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonylamino, cyclopropylcarbonylamino, cyclohexylcarbonylamino, adamantylcarbonylamino, benzoylamino, 1- or 2-naphthoylamino, 1-indenecarbonylamino, phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N,N-diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino, N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino, N-butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino, N-isonicotinoyl-N-hexylamino or 4-trifluoromethylphenylcarbamoylamino, is preferably an amino group (which may be substituted one or two C1-C10 alkyl or C1-C7 aliphatic acyl groups), more preferably an amino group (which may be substituted with one or two C1-C6 alkyl groups or C1-C2 aliphatic acyl groups).
From the above-mentioned definition for the substituents xcex1 and xcex2, in the case where R1 represents a xe2x80x9ccarbamoyl group (which may have one or two substituents xcex1)xe2x80x9d, the group having the substituent may include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, s-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, decylcarbamoyl, (trifluoromethyl)carbamoyl, (tetrafluoropropyl)carbamoyl, cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, adamantylcarbamoyl, phenylcarbamoyl, methylphenylcarbamoyl, isopropylphenylcarbamoyl, diisopropylphenylcarbamoyl, triisopropylphenylcarbamoyl, 2-, 3- or 4-(trifluoromethyl)phenylcarbamoyl, 2-, 3- or 4-methoxyphenylcarbamoyl, fluorophenylcarbamoyl, difluorophenylcarbamoyl, trifluorophenylcarbarnoyl, 2-, 3- or 4-chlorophenylcarbamoyl, difluorophenylcarbamoyl, hydroxyphenylcarbamoyl, 2,5dimethyl-4-hydroxyphenylcarbamoyl, 2,5-t-butyl-4-hydroxyphenylcarbamoyl, cyanophenylcarbamoyl, nitrophenylcarbamoyl, cyclopropylphenylcarbamoyl, cyclohexylphenylcarbamoyl, adamantylphenylcarbamoyl, biphenylcarbamoyl, benzylphenylcarbamoyl, acetylphenylcarbamoyl, acetyloxyphenylcarbamoyl, aminophenylcarbamoyl, dimethylaminophenylcarbamoyl, diethylaminophenylcarbamoyl, methylenedioxyphenylcarbamoyl, ethylenedioxyphenylcarbamoyl, 1- or 2-naphthylcarbamoyl, benzylcarbamoyl, methylbenzylcarbamoyl, isopropylbenzylcarbamoyl, diisopropylbenzylcarbamoyl, triisopropylbenzylcarbamoyl, (trifluoromethyl)benzylcarbamoyl, methoxybenzylcarbamoyl, fluorobenzylcarbamoyl, difluorobenzylcarbamoyl, trifluorobenzylcarbamoyl, 2-, 3- or 4-chlorobenzylcarbamoyl, dichlorobenzylcarbamoyl, hydroxybenzylcarbamoyl, cyanobenzylcarbamoyl, nitrobenzylcarbamoyl, cyclopropylbenzylcarbamoyl, cyclohexylbenzylcarbamoyl, adamantylbenzylcarbamoyl, phenylbenzylcarbamoyl, benzylbenzylcarbamoyl, acetylbenzylcarbamoyl, acetyloxybenzylcarbamoyl, aminobenzylcarbamoyl, dimethylaminobenzylcarbamoyl, methylenedioxybenzylcarbamoyl, phenethylcarbamoyl, (trifluoromethyl)phenethylcarbamoyl, fluorophenethylcarbamoyl, cyclopropylcarbonylcarbamoyl, cyclohexylcarbonylcarbamoyl, adamantylcarbonylcarbamoyl, benzoylcarbamoyl, phenylacetylcarbamoyl, 4-phenylbutylcarbamoyl, pyrrolylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, 2-, 3- or 4-pyridylcarbamoyl, pyrrolylcarbonylcarbamoyl, furylcarbonylcarbamoyl, thienylcarbonylcarbamoyl, nicotinoylcarbamoyl, methanesulfonylcarbamoyl, trifluoromethylcarbamoyl, benzenesulfonylcarbamoyl, toluenesulfonylcarbamoyl or benzylsulfonylcarbamoyl, is preferably a carbamoyl group which may have one substituent xcex1, more preferably a carbamoyl group which may be substituted with one group selected from a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C10 aryl group which may have from 1 to 3 substituents xcex3, or an aralkyl group consisting of a C1-C6 alkyl group which is substituted by a C6-C10 aryl group, which itself may have from 1 to 3 substituents xcex3.
In the case where R1 represents a xe2x80x9cthiocarbamoyl group (which may have one or two substituents xcex1)xe2x80x9d, the group having the substituent may include methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl, isopropylthiocarbamoyl, butylthiocarbamoyl, s-butylthiocarbamoyl, t-butylthiocarbamoyl, pentylthiocarbamoyl, hexylthiocarbamoyl, decylthiocarbamoyl, cyclopropylthiocarbamoyl, cyclopentylthiocarbamoyl, cyclohexylthiocarbamoyl, adamantylthiocarbamoyl, phenylthiocarbamoyl, methylphenylthiocarbamoyl, isopropylphenylthiocarbamoyl, diisopropylphenylthiocarbamoyl, triisopropylphenylthiocarbamoyl, 2-, 3- or 4-(trifluoromethyl)phenylthiocarbamoyl, 2- 3- or 4-methoxyphenylthiocarbamoyl, fluorophenylthiocarbamoyl, difluorophenylthiocarbamoyl, trifluorophenylthiocarbamoyl, 2-, 3- or 4-chlorophenylthiocarbamoyl, dichlorophenylthiocarbamoyl, 2,5-dimethyl-4-hydroxyphenylthiocarbamoyl, 2,5-t-butyl-4-hydroxyphenylthiocarbamoyl, hydroxyphenylthiocarbamoyl, cyanophenylthiocarbamoyl, nitrophenylthiocarbamoyl, cyclohexylphenylthiocarbamoyl, adamantylphenylthiocarbamoyl, biphenylthiocarbamoyl, benzylphenylthiocarbamoyl, acetylphenylthiocarbamoyl, acetyloxyphenylthiocarbamoyl, aminophenylthiocarbamoyl, dimethylaminophenylthiocarbamoyl, methylenedioxyphenylthiocarbamoyl, 1- or 2-naphthylthiocarbamoyl, benzylthiocarbamoyl, methylbenzylthiocarbamoyl, isopropylbenzylthiocarbamoyl, diisopropylbenzylthiocarbamoyl, triisopropylbenzylthiocarbamoyl, (trifluoromethylbenzyl)thiocarbamoyl, fluorobenzylthiocarbamoyl, difluorobenzylthiocarbamoyl, trifluorobenzylthiocarbamoyl, 2-, 3- or 4-chlorobenzylthiocarbamoyl, dichlorobenzylthiocarbamoyl, hydroxybenzylthiocarbamoyl, cyanobenzylthiocarbamoyl, nitrobenzylthiocarbamoyl, cyclopropylbenzylthiocarbamoyl, cyclohexylbenzylthiocarbamoyl, adamantylbenzylthiocarbamoyl, acetylbenzylthiocarbamoyl, acetyloxybenzylthiocarbamoyl, aminobenzylthiocarbamoyl, dimethylaminobenzylthiocarbamoyl, methylenedioxybenzylthiocarbamoyl, cyclopropylcarbonylthiocarbamoyl, cyclohexylcarbonylthiocarbamoyl, adamantylcarbonylthiocarbamoyl, benzoylthiocarbamoyl, phenylacetylthiocarbamoyl, 2-, 3- or 4-pyridylthiocarbamoyl, nicotinoylthiocarbamoyl, methanesulfonylthiocarbamoyl, trifluoromethylthiocarbamoyl, benzenesulfonylthiocarbamoyl, toluenesulfonylthiocarbamoyl or benzylsulfonylthiocarbamoyl, is preferably a thiocarbamoyl group which may have one substituent xcex1, and more preferably a thiocarbamoyl group which may be substituted with one group selected from a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3) and a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion).
In the case where R1 represents a xe2x80x9csulfonyl group having one substituent xcex1xe2x80x9d, the group may include methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, s-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl, hexanesulfonyl, cyclopropanesulfonyl, cyclopentanesulfonyl, cyclohexanesulfonyl, adamantanesulfonyl, benzenesulfonyl, toluenesulfonyl, isopropylbenzenesulfonyl, diisopropylbenzenesulfonyl, triisopropylbenzenesulfonyl, (trifluoromethyl)benzenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, hydroxybenzenesulfonyl, cyanobenzenesulfonyl, nitrobenzenesulfonyl, cyclohexylbenzenesulfonyl, adamantylbenzensulfonyl, acetylbenzenesulfonyl, acetyloxybenzenesulfonyl, aminobenzenesulfonyl, dimethylaminobenzenesulfonyl, methylenedioxybenzenesulfonyl, 1- or 2-naphthalenesulfonyl, phenylmethylsulfonyl or pyridinesulfonyl, and is preferably a sulfonyl group which is substituted with one group selected from a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), or with a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion).
In the case where R1 represents a xe2x80x9ccarbonyl group which has one substituent xcex1xe2x80x9d, the group having the substituent may include acetyl, propionyl, butyryl, isopropylcarbonyl, butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, pentylcarbonyl, hexylcarbonyl, decylcarbonyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, phenylcarbonyl, methylphenylcarbonyl, isopropylphenylcarbonyl, diisopropylphenylcarbonyl, triisopropylphenylcarbonyl, 2-, 3- or 4-(trifluoromethylphenyl)carbonyl, 2-, 3- or 4-methoxyphenylcarbonyl, fluorophenylcarbonyl, difluorophenylcarbonyl, trifluorophenylcarbonyl, 2-, 3- or 4-chlorophenylcarbonyl, dichlorophenylcarbonyl, 2,5-dimethyl-4-hydroxyphenylcarbonyl, 2,5-t-butyl4-hydroxyphenylcarbonyl, hydroxyphenylcarbonyl, cyanophenylcarbonyl, nitrophenylcarbonyl, cyclohexylphenylcarbonyl, adamantylphenylcarbonyl, biphenylcarbonyl, benzylphenylcarbonyl, acetylphenylcarbonyl, acetyloxyphenylcarbonyl, aminophenylcarbonyl, dimethylaminophenylcarbonyl, methylenedioxyphenylcarbonyl, 1- or 2-naphthylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl, isopropylbenzylcarbonyl, diisopropylbenzylcarbonyl, triisopropylbenzylcarbonyl, (trifluoromethyl)benzylcarbonyl, fluorobenzylcarbonyl, difluorobenzylcarbonyl, trifluorobenzylcarbonyl, 2-, 3- or 4-chlorobenzylcarbonyl, dichlorobenzylcarbonyl, hydroxybenzylcarbonyl, cyanobenzylcarbonyl, nitrobenzylcarbonyl, cyclopropylbenzylcarbonyl, cyclohexylbenzylcarbonyl, adamantylbenzylcarbonyl, acetylbenzylcarbonyl, acetyloxybenzylcarbonyl, aminobenzylcarbonyl, dimethylaminobenzylcarbonyl, methylenedioxybenzylcarbonyl, cyclopropylcarbonylcarbonyl, cyclohexylcarbonylcarbonyl, adamantylcarbonylcarbonyl, benzoylcarbonyl, phenylacetylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, nicotinoylcarbonyl, methanesulfonylcarbonyl, trifluoromethylcarbonyl, benzenesulfonylcarbonyl, toluenesulfonylcarbonyl or benzylsulfonylcarbonyl, and is preferably a carbonyl group which, may be substituted with one group selected from a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3) and a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion).
In the case where R2, R3 or L represents a xe2x80x9cC6-C10 aryl group (which may have from 1 to 3 substituents xcex2)xe2x80x9d, the group having the substituents may include methylphenyl, isopropylphenyl, (trifluoromethyl)phenyl, methoxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, biphenyl, benzylphenyl, cyanophenyl, nitrophenyl, aminophenyl, dimethylaminophenyl, diethylaminophenyl or 1- or 2-naphthyl, is preferably a phenyl group (which may have from 1 to 3 substituents xcex2), more preferably a phenyl group (which may have one or two substituents xcex2), and most preferably a phenyl group (which may be substituted by one substituent xcex2).
In the case where R2, R3 or L represents a xe2x80x9cC7-C16 aralkyl group (which may have from 1 to 3 substituents xcex2 on the aryl portion)xe2x80x9d, the group having the substituents may include methylbenzyl, isopropylbenzyl, (trifluoromethyl)benzyl, methoxybenzyl, fluorobenzyl, chlorobenzyl, hydroxybenzyl, phenylbenzyl, cyanobenzyl, nitrobenzyl, aminobenzyl, dimethylaminobenzyl, methylphenethyl, isopropylphenethyl, (trifluoromethyl)phenethyl, methoxyphenethyl, fluorophenethyl, chlorophenethyl, hydroxyphenethyl, phenylphenethyl, cyanophenethyl, nitrophenethyl, aminophenethyl, dimethylaminophenethyl, methylnaphthylmethyl, isopropylnaphthylmethyl, (trifluoromethyl)naphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl, chloronaphthylmethyl, hydroxynaphthylmethyl, cyanonaphthylmethyl, nitronaphthylmethyl, aminonaphthylmethyl or dimethylaminonaphthylmethyl, is preferably a phenyl-C1-C6 alkyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion), more preferably a phenyl-C1-C4 alkyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion), still more preferably a phenyl-C1-C2 alkyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion), and most preferably a phenyl-C1-C2 alkyl group (which may have one substituent xcex2 on the phenyl portion).
The amine derivative compound of the present compound of formula (I) can be converted to a salt according to a conventional method. Such salt may include inorganic salts, for example alkali metal salts such as a sodium salt a potassium salt and a lithium salt; alkaline earth metals such as a calcium salt and a magnesium salt; metal salts such as an aluminum salt, an iron salt, a zinc salt, a copper salt, a nickel salt and a cobalt salt; an ammonium salt; amine salts such as organic salts, e.g., a t-octylamine salt, a dibenzylamine salt, a morpholine salt, a glucosamine salt, a phenylglycine alkyl ester salt, an ethylenediamine salt, a N-methylglucamine salt, a guanidine salt, a diethylamine salt, a triethylamine salt, a dicyclohexylamine salt, a N,Nxe2x80x2-dibenzylethylenediamine salt, a chloroprocaine salt, a procaine salt, a diethanolamine salt, a N-benzyl-N-phenethylamine salt, a piperazine salt, a tetramethylammonium salt and a tris(hydroxymethyl)aminomethane salt; an inorganic acid salt, for example a hydrohalogenic acid salt such as a hydrofluoride, a hydrochloride, a hydrobromide and a hydroiodide; a nitrite, a perchlorate, a sulfate and a phosphate; a salt of an organic acid, for example a lower alkanesulfonate such as a methanesulfonate, trifluoromethanesulfonate and ethanesulfonate salt; an arylsulfonate such as a benzenesulfonate and p-toluenesulfonate salt; a salt of an amino acid such as a glutamate and an aspartate; a carboxylate such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and amino acid salts such as ornithinate, glutamate and aspartate, more preferably a hydrohalogenic acid salt and an organic acid salt.
Various isomers are included in the compound of the present invention. For example, a thiazolidine ring and an oxazolidine ring of the amine derivative compound of the above formula (I) include an asymmetric carbon, and since an asymmetric carbon sometimes exists on a substituent group, such compounds have optical isomers.
That is, stereoisomers of R-configuration and S-configuration exist in the amine derivative compound of the above formula (I). Each of the respective stereoisomers or compounds containing such stereoisomers in an arbitrary proportion are all included in the present invention. Such stereoisomers can be obtained by synthesizing the amine derivative compound of the compound (I) by using an optically active starting material or by subjecting the synthesized amine derivative compound of the compound (I) to optical resolution, as necessary, using a conventional optical resolution or separation method.
The amine derivative compound of the compound (I) of the present invention absorbs moisture when it is left to stand in the atmosphere or recrystallized to carry adsorbed water or to be hydrated. Such compounds are also included in the present invention in the case they form hydrates.
The amine derivative compound of the compound (I) of the present invention sometimes absorbs other certain kinds of solvents to form a solvate and such a solvate is also included in the present invention.
Moreover, the present invention also includes all so-called prodrugs which are compounds that are metabolized in the living body and converted to the amine derivative compounds or their pharmacologically acceptable salts of the compound of formula (I) of the present invention.
The amine derivative compounds or their pharmacologically acceptable salts of the compound of formula (I) of the present invention may be used together with another drug (i.e., active agent), and particularly with sulfonylurea agents, xcex1-glucosidase inhibitory agents, aldose reductase inhibitory agents, biguanide agents, statin type compounds, squalene synthesis inhibitory agents, fibrate type compounds, LDL disassimilation promoters, angiotensin II antagonists, angiotensin converting enzyme inhibitory agents, antitumor agents and FBPase inhibitory agents.
Among the above, sulfonylurea agents refer to drugs that promote the secretion of insulin, examples of which include tolbutamide, acetohexamide, tolazamide and chlorpropamide.
Among the above, xcex1-glucosidase inhibitory agents refer to drugs that inhibit digestive enzymes such as amylase, maltase, xcex1-dextrinase and squalase and have the effect of delaying digestion of starch and sucrose, examples of which include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (generic name: voglibose) and migritol.
Among the above, aldose reductase inhibitory agents refer to drugs that inhibit diabetic complications by inhibiting the rate-determining enzyme of the first step of the polyol route, examples of which include tolrestat, epalrestat, 2,7-difluoro-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (generic name: imirestat), 3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazoline acetate (generic name: zenarestat), 6-fluoro-2,3-dihydro-2xe2x80x2,5xe2x80x2-dioxo-spiro[4H-1-benzopyran-4,4xe2x80x2-imidazolidine]-2-carboxamide (SNK-860), zopolurestat, sorbinil and 1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209).
Among the above, biguanide agents refer to drugs having, effects such as anaerobic glycolysis promoting effects, enhancement of peripheral insulin effects, suppression of absorption of glucose from the intestinal tract, suppression of liver glyconeogenesis and inhibition of fatty acid oxidation, examples of which include fenformin, metformin and buformine.
Among the above, statin type compounds refer to drugs that lower blood cholesterol by inhibiting hydroxymethylglutaryl CoA (HMG-CoA) reductase, examples of which include pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin.
Among the above, squalene synthesis inhibitory agents refer to drugs that lower blood cholesterol by inhibiting squalene synthesis, examples of which include (S)-xcex1-[bis(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl-3-phenoxybenzene butanesulfonate monopotassium salt (BMS-188494).
Among the above, fibrate type compounds refer to drugs that lower blood triglycerides by inhibiting triglyceride synthesis and secretion in the liver and activating lipoprotein lipase, examples of which include bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate, clofibrate, clofibrinic acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate, lonifibrate, simfibrate and theofibrate.
Among the above, LDL disassimilation promoters refer to drugs that lower blood cholesterol by increasing LDL (low-density lipoprotein) receptors, examples of which include the compound described in Japanese Patent Application (Kokai) No. Hei 7-346144 or its salt, and more specifically, N-{2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl}-7,7-diphenyl-2,4,6-heptatrienic acid amide.
The above-mentioned statin type compounds, squalene synthesis inhibitory agents, fibrate type compounds and LDL disassimilation promoters may be substituted with other drugs that have the effects of lowering blood cholesterol and triglycerides. Examples of such drugs include nicotinic acid derivative such as nicomol and niceritrol, antioxidants such as probucol, and ion exchange resins such as colestyramine.
Among the above, angiotensin II antagonists refer to drugs that lower blood pressure by strongly suppressing elevation of blood pressure caused by angiotensin II. Examples of such drugs include losartan potassium, candesartan, cilexetil, valsartan, termisartan and ormesartan.
Among the above, angiotensin converting enzyme inhibitory agents refer to drugs that partially lower blood sugar in diabetes patients while simultaneously lowering blood pressure by inhibiting angiotensin convertase, examples of which include captopril, enalapril, alacepril, delapril, lamipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalapril maleate, fosinopril, mobertopril, perindopril, quinapril, spirapril, temocapril and trandolapril.
Among the above, FBPase inhibitory agents refer to diabetes therapeutic and/or preventing agents that are drugs having an inhibitory effect on fructose-1,6-bisphosphatase (FBPase), which is a rate-determining enzyme of glyconeogenesis in the liver.
The amine derivative compound of the above formula (I) may preferably include
(1) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which may have one substituent xcex1), a thiocarbamoyl group (which may have one substituent xcex1), a sulfonyl group (which has one substituent xcex1) or a carbonyl group (which has one substituent xcex1);
(2) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which has one substituent xcex1), a thiocarbamoyl group (which has one substituent xcex1), a sulfonyl group (which has one substituent xcex1) or a carbonyl group (which has one substituent xcex1);
(3) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which has one substituent xcex1), a thiocarbamoyl group (which has one substituent xcex1) or a carbonyl group (which has one substituent xcex1);
(4) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which has one substituent xcex1);
(5) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a thiocarbamoyl group (which has one substituent xcex1);
(6) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbonyl group (which has one substituent xcex1);
(7) the amine derivative compound or pharmacologically acceptable salt thereof in which R2 represents a hydrogen atom, a C1-C10 alkyl group, a phenyl group (which may have from 1 to 3 substituents xcex2) or a benzyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion);
(8) the amine derivative compound or pharmacologically acceptable salt thereof in which R2 represents a hydrogen atom, a C1-C10 alkyl group, a phenyl group (which may have one substituent xcex2) or a benzyl group (which may have one substituent xcex2 on the phenyl portion);
(9) the amine derivative compound or pharmacologically acceptable salt thereof in which R2 represents a hydrogen atom or a C1-C10 alkyl group;
(10) the amine derivative compound or pharmacologically acceptable salt thereof in which R2 represents a hydrogen atom or a C1-C6 alkyl group;
(11) the amine derivative compound or pharmacologically acceptable salt thereof in which R2 represents a hydrogen atom;
(12) the amine derivative compound or pharmacologically acceptable salt thereof in which R2 represents a C1-C6 alkyl group;
(13) the amine derivative compound or pharmacologically acceptable salt thereof in which R3 represents a hydrogen atom, a C1-C6 alkyl group, a phenyl group (which may have from 1 to 3 substituents xcex2) or a benzyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion);
(14) the amine derivative compound or pharmacologically acceptable salt thereof in which R3 represents a hydrogen atom, a C1-C6 alkyl group, a phenyl group (which may have one substituent xcex2) or a benzyl group (which may have one substituent xcex2 on the phenyl portion);
(15) the amine derivative compound or pharmacologically acceptable salt thereof in which R3 represents a hydrogen atom or a C1-C4 alkyl group;
(16) the amine derivative compound or pharmacologically acceptable salt thereof in which R3 represents a C1-C2 alkyl group;
(17) the amine derivative compound or pharmacologically acceptable salt thereof in which R3 represents a methyl group;
(18) the amine derivative compound or pharmacologically acceptable salt thereof in which W1, W2 and W3 each represent a single bond or a C1-C6 alkylene group;
(19) the amine derivative compound or pharmacologically acceptable salt thereof in which W1, W2 and W3 each represent a single bond or a C1-C4 alkylene group;
(20) the amine derivative compound or pharmacologically acceptable salt thereof in which W1 and W2 each represent a single bond or a C1-C4 alkylene group, and W3 represents a C1-C2 alkylene group;
(21) the amine derivative compound or pharmacologically acceptable salt thereof in which W1 and W2 each represent a single bond or a C1-C2 alkylene group, and W3 represents a methylene group;
(22) the amine derivative compound or pharmacologically acceptable salt thereof in which W1 and W2 represent a single bond and W3 represents a methylene group;
(23) the amine derivative compound or pharmacologically acceptable salt thereof in which X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom and Q represents a sulfur atom;
(24) the amine derivative compound or pharmacologically acceptable salt thereof in which X represents an oxygen atom, Y represents an oxygen atom and Q represents a sulfur atom;
(25) the amine derivative compound or pharmacologically acceptable salt thereof in which Z represents a xe2x95x90CHxe2x80x94 group;
(26) the amine derivative compound or pharmacologically acceptable salt thereof in which Z represents a nitrogen atom;
(27) the amine derivative compound or pharmacologically acceptable salt thereof in which Ar represents a naphthalene ring;
(28) the amine derivative compound or pharmacologically acceptable salt thereof in which Ar represents a benzene ring;
(29) the amine derivative compound or pharmacologically acceptable salt thereof in which L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom, a C1-C6 alkyl group, a phenyl group (which may have from 1 to 3 substituents xcex2) or a benzyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion);
(30) the amine derivative compound or pharmacologically acceptable salt thereof in which L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom, a C1-C6 alkyl group, a phenyl group (which may have from 1 to 3 substituents xcex2) or a benzyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion);
(31) the amine derivative compound or pharmacologically acceptable salt thereof in which L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom or a C1-C6 alkyl group;
(32) the amine derivative compound or pharmacologically acceptable salt thereof in which L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom or a C1-C4 alkyl group;
(33) the amine derivative compound or pharmacologically acceptable salt thereof in which each L represents a hydrogen atom;
(34) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents (i) a C1-C10 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a phenyl-C1-C6 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), (v) a phenylcarbonyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), (vi) an aromatic heterocyclic group (which may have from 1 to 3 substituents xcex3), (vii) a C1-C4 alkylsulfonyl group, (viii) a C1-C4 halogenoalkylsulfonyl group or (ix) a phenylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion);
(35) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents (i) a C1-C8 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a phenyl-C1-C4 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), (v) a pyridyl group, (vi) a methanesulfonyl group, (vii) a trifluoromethanesulfonyl group or (viii) a phenylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion);
(36) the amine derivative compound or pharmacologically acceptable salt thereof in which a substituent cc represents (i) a C1-C8 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a phenyl-C1-C4 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), (v) a pyridyl group or (vi) a phenylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion);
(37) the amine derivative compound or pharmacologically acceptable salt thereof in which the substituent xcex1 represents (i) a C1-C4 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a benzyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion) or (v) a pyridyl group;
(38) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents (i) a C1-C4 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3) or (iv) a pyridyl group;
(39) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents a C1-C4 alkyl group;
(40) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents a C5-C10 cycloalkyl group;
(41) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents a phenyl group (which may have from 1 to 3 substituents xcex3);
(42) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex1 represents a pyridyl group;
(43) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex2 represents (i) a C1-C4 alkyl group, (ii) a C1-C2 halogenoalkyl group, (iii) a C1-C4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group or (viii) an amino group (which may have one or two substituents xcex4);
(44) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex2 represents (i) a C1-C4 alkyl group, (ii) a trifluoromethyl group, (iii) a C1-C2 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group or (vi) an amino group;
(45) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex2 represents (i) a C1-C4 alkyl group, (ii) a halogen atom or (iii) a hydroxyl group;
(46) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a C1-C4 halogenoalkyl group, (iii) a C1-C6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a phenyl group, (ix) a benzyl group, (x) a C1-C5 aliphatic acyl group, (xi) an amino group or (xii) a C1-C4 alkylenedioxy group;
(47) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a C1-C2 halogenoalkyl group, (iii) a C1-C4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a C1-C2 aliphatic acyl group or (ix) a C1-C4 alkylenedioxy group;
(48) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a trifluoromethyl group, (iii) a C1-C4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a C1-C2 aliphatic acyl group or (ix) a C1-C4 alkylenedioxy group;
(49) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex3 represents (i) a C1-C4 alkyl group, (ii) a trifluoromethyl group, (iii) a halogen atom or (iv) a nitro group;
(50) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex3 represents a C1-C4 alkyl group or a halogen atom;
(51) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex4 represents (i) a C1-C4 alkyl group, (ii) a phenyl group, (iii) a benzyl group, (iv) a C1-C5 aliphatic acyl group or (v) a benzoyl group;
(52) the amine derivative compound or pharmacologically acceptable salt thereof in which substituent xcex4 represents a C1-C4 alkyl group or a C1-C2 aliphatic acyl group.
In the amine derivative compound of the above formula (I), preferred are the compounds in which R1 is selected from (1) to (6), R2 is selected from (7) to (12), R3 is selected from (13) to (17), W1, W2 and W3 are selected from (18) to (22), X, Y and Q are selected from (23) and (24), Z is selected from (25) and (26), Ar is selected from (27) and (28), L is selected from (29) to (33), substituent xcex1 is selected from (34) to (42), substituent xcex2 is selected from (43) to (45), substituent xcex3 is selected from (46) to (50) and substituent xcex4 is selected from (51) and (52) and used in appropriate combination.
For example, in the amine derivative compound of the above formula (I), the following compounds are also preferred:
(53) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which may have one substituent xcex1), a thiocarbamoyl group (which may have one substituent xcex1), a sulfonyl group (which has one substituent xcex1) or a carbonyl group (which has one substituent xcex1);
R2 represents a hydrogen atom, a C1-C10 alkyl group, a phenyl group (which may have one substituent xcex2) or a benzyl group (which may have one substituent xcex2 on the phenyl portion);
R3 represents a hydrogen atom, a C1-C6 alkyl group, a phenyl group (which may have one substituent xcex2) or a benzyl group (which may have one substituent xcex2 on the phenyl portion);
W1, W2 and W3 each represent a single bond or a C1-C4 alkylene group;
X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom and Q represents a sulfur atom;
Z represents a xe2x95x90CHxe2x80x94 group;
Ar represents a benzene ring;
L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom, a C1-C6 alkyl group, a phenyl group (which may have from 1 to 3 substituents xcex2) or a benzyl group (which may have from 1 to 3 substituents xcex2 on the phenyl portion);
substituent xcex1 represents (i) a C1-C8 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a phenyl C1-C4 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), (v) a pyridyl group, (vi) a methanesulfonyl group, (vii) a trifluoromethanesulfonyl group or (viii) a phenylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion);
substituent xcex2 represents (i) a C1-C4 alkyl group, (ii) a trifluoromethyl group, (iii) a C1-C2 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group or (vi) an amino group; and
substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a C1-C4 halogenoalkyl group, (iii) a C1-C6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a phenyl group, (ix) a benzyl group, (x) a C1-C5 aliphatic acyl group, (xi) an amino group or (xii) a C1-C4 alkylenedioxy group;
(54) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which has one substituent xcex1), a thiocarbamoyl group (which has one substituent xcex1), a sulfonyl group (which has one substituent xcex1) or a carbonyl group (which has one substituent xcex1);
R2 represents a hydrogen atom or a C1-C10 alkyl group;
R3 represents a hydrogen atom or a C1-C4 alkyl group;
W1 and W2 each represent a single bond or a C1-C4 alkylene group and W3 represents a C1-C2 alkylene group;
X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom and Q represents a sulfur atom;
Z represents a xe2x95x90CHxe2x80x94 group;
Ar represents a benzene ring;
L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom or a C1-C4 alkyl group;
substituent xcex1 represents (i) a C1-C8 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a phenyl-C1-C4 alkyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion), (v) a pyridyl group or (vi) a phenylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion); and
substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a trifluoromethyl group, (iii) a C1-C4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a C1-C2 aliphatic acyl group or (ix) a C1-C4 alkylenedioxy group;
(55) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which has one substituent xcex1), a thiocarbamoyl group (which has one substituent xcex1) or a carbonyl group (which has one substituent xcex1);
R2 represents a hydrogen atom;
R3 represents a C1-C2 alkyl group;
W1 and W2 each represent a single bond or a C1-C2 alkylene group and W3 represents a methylene group;
X represents an oxygen atom, Y represents an oxygen atom and Q represents a sulfur atom;
Z represents a xe2x95x90CHxe2x80x94 group;
Ar represents a benzene ring;
L represents a hydrogen atom;
substituent xcex1 represents (i) a C1-C4 alkyl group, (ii) a C5-C10 cycloalkyl group, (iii) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (iv) a benzyl group (which may have from 1 to 3 substituents xcex3 on the phenyl portion) or (v) a pyridyl group; and
substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a C1-C2 halogenoalkyl group, (iii) a C1-C4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group, (viii) a C1-C2 aliphatic acyl group or (ix) a C1-C4 alkylenedioxy group.
Further, in the amine derivative compound of the above formula (I), the following compounds are preferable:
(56) the amine derivative compound or pharmacologically acceptable salt thereof in which R1 represents a carbamoyl group (which may have one or two substituents xcex1), a thiocarbamoyl group (which may have one or two substituents xcex1) or a sulfonyl group (which has one substituent xcex1);
R2 and R3 represent a hydrogen atom, a C1-C10 alkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex2) or a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex2 on the aryl portion) respectively;
W1, W2 and W3 each represent a single bond or a C1-C8 alkylene group;
X, Y and Q each represent an oxygen atom or a sulfur atom;
Z represents a xe2x95x90CHxe2x80x94 group or a nitrogen atom;
Ar represents a benzene ring or a naphthalene ring;
L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom, a C1-C6 alkyl group, a C6-C10 aryl group (which may have from 1 to 3 substituents xcex2) or a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex2 on the aryl portion);
substituent xcex1 represents (i) a C1-C10 alkyl group, (ii) a C1-C6 halogenoalkyl group, (iii) a C3-C10 cycloalkyl group, (iv) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex3), (v) a C7-C16 aralkyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion), (vi) a C4-C11 cycloalkylcarbonyl group, (vii) a C7-C11 arylcarbonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion), (viii) a C8-C17 aralkylcarbonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion), (ix) an aromatic heterocyclic group (which may have from 1 to 3 substituents xcex3), (x) a aromatic heterocyclic carbonyl group (which may have from 1 to 3 substituents xcex3), (xi) a C1-C6 alkylsulfonyl group, (xii) a C1-C6 halogenoalkylsulfonyl group, (xiii) a C6-C10 arylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion) or (xiv) a C7-C16 aralkylsulfonyl group (which may have from 1 to 3 substituents xcex3 on the aryl portion);
substituent xcex2 represents (i) a C1-C6 alkyl group, (ii) a C1-C6 halogenoalkyl group, (iii) a C1-C6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a C6-C10 aryl group (which may have from 1 to 3 substituents xcex4), (vii) a C7C16 aralkyl group (which may have from 1 to 3 substituents xcex4 on the aryl portion), (viii) a cyano group, (ix) a nitro group or (x) an amino group (which may have one or two substituents xcex4);
substituent xcex3 represents (i) a C1-C6 alkyl group, (ii) a C1-C6 halogenoalkyl group, (iii) a C1-C6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano group; (vii) a nitro group, (viii) a C3-C10 cycloalkyl group, (ix) a C6-C10 aryl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents), (x) a C7-C16 aralkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents on the aryl moiety), (xi) a C1-C7 aliphatic acyl group, (xii) a C1-C7 aliphatic acyloxy group, (xiii) an amino group, (xiv) a di-(C1-C6 alkyl)amino group or (xv) a C1-C4 alkylenedioxy group; and
substituent xcex4 represents (i) a C1-C10 alkyl group, (ii) a C6-C10 aryl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents), (iii) a C7-C16 aralkyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents on the aryl moiety), (iv) a C1-C7 aliphatic acyl group, (v) a C4-C11 cycloalkylcarbonyl group, (vi) a C7-C11 arylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents), (vii) a C8-C17 aralkylcarbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents on the aryl moiety) or (viii) an aromatic heterocyclic carbonyl group (which may have from 1 to 3 C1-C6 alkyl groups, C1-C6 halogenoalkyl groups, C1-C6 alkoxy groups or halogen atoms as the substituents).
The compound of the present invention may include the compounds listed in Table 1 to Table 6 but the present invention is not limited to these compounds.
The compounds listed in Table 1 and Table 2 have the structural formula (I-1) and the compounds listed in Table 3 to Table 6 have the structural formulae (I-2) to (I-5) respectively. The abbreviations in the Tables mean the following: Ac: acetyl group, Ada(1): 1-adamantyl group, Ada(1)c: 1-adamantylcarbonyl group, Boz: benzoyl group, Bu: butyl group, tBu: t-butyl group, Bz: benzyl group, EdO: ethylenedioxy group, Et: ethyl group, Hx: hexyl group, cHx: cyclohexyl group, cHxc: cyclohexylcarbonyl group, MdO: methylenedioxy group, Me: methyl group, Nic: nicotinoyl group, iNic: isonicotinoyl group, Np: naphthyl group, Ph: phenyl group, cPn: cyclopentyl group, cPnc: cyclopentylcarbonyl group, Pr: propyl group, cPrc: cyclopropylcarbonyl group, iPr: isopropyl group, Pyr: pyridyl group, and E. C. N.: exemplification compound number.
In the above Tables, the present compounds preferably include those of exemplification compound Nos.:
(1-2) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-ethylurea,
(1-8) 1-(adamant-1-yl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
(1-9) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
(1-59) 1-(2,4-difluorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
(1-165) 1-(adamant-1-yl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea,
(1-172) 1-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-3-[4-(trifluoromethyl)phenyl]urea,
(1-174) 1-(2,4-difluorophenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]urea,
(1-192) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-nitrophenyl)urea,
(1-196) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-1-n-hexyl-3-phenylurea,
(1-202) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl-1-n-hexyl-3-[4-(trifluoromethyl)phenyl]urea,
(1-203) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl-1-n-hexyl-3-(4-fluorophenyl)urea,
(1-210) 1-(adamant-1-yl)-3-(7-[2-[4-(2,4dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
(1-213) 1-(2,6-diisopropylphenyl)-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
(1-217) 1-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)-3-[4-(trifluoromethyl)phenyl]urea,
(1-223) 1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
(1-232) 1-[4-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
(1-284) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea,
(1-299) 1-benzyl-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)thiourea,
(1-300) 1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)thiourea,
(1-312) 1-(4-chlorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)thiourea,
(1-316) N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)methanesulfonamide,
(2-5) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-n-hexylurea,
(2-9) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
(2-24) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
(2-26) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
(2-29) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
(2-41) 1-(3-cyanophenyl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
(2-82) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-trifluoromethyl)benzylurea,
(2-190) 1-(2-t-butyl-5-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxymethyl]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
(3-70) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-3-methyl-3H-imidazo[4,5-b]pyridin-5-ylthio]-2,6-dimethylphenyl)-3-[4-(trifluoromethyl)phenyl]urea,
(6-1) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
(6-4) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]-N-n-hexylacetamide,
(6-7) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]cyclopentanecarboxylic acid amide,
(6-8) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]cyclohexanecarboxylic acid amide,
(6-10) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-11) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]naphthalene-2-carboxylic acid amide,
(6-19) 2,4difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-21) 3-chloro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-36) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
(6-37) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]isonicotinamide,
(6-51) 3,5-di-t-butyl-N-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-4-hydroxybenzamide,
(6-56) 2-(3-chlorophenyl)-N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]acetamide, and
(6-59) N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]nicotinamide,
or pharmacologically acceptable salts thereof.
More preferably, they include those of exemplification compound Nos.:
(1-2) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-ethylurea,
(1-8) 1-(adamant-1-yl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
(1-9) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
(1-174) 1-(2,4-difluorophenyl)-3-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]urea,
(1-192) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-nitrophenyl)urea,
(1-203) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl-1-n-hexyl-3-(4-fluorophenyl)urea,
(1-213) 1-(2,6-diisopropylphenyl)-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
(1-223) 1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
(1-284) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea,
(1-300) 1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)thiourea,
(1-312) 1-(4-chlorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)thiourea,
(1-316) N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)methanesulfonamide,
(2-9) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
(2-24) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
(2-26) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
(2-29) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
(2-82) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)benzyl]urea,
(6-1) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
(6-4) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]-N-n-hexylacetamide,
(6-7) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]cyclopentanecarboxylic acid amide,
(6-10) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-11) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]naphthalene-2-carboxylic acid amide,
(6-19) 2,4-difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-21) 3-chloro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-36) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
(6-37) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]isonicotinamide,
(6-51) 3,5-di-t-butyl-N-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-4-hydroxybenzamide,
(6-56) 2-(3-chlorophenyl)-N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]acetamide, and
(6-59) N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]nicotinamide,
or pharmacologically acceptable salts thereof.
Most preferably, they include those of exemplification compound Nos.:
(1-2) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-ethylurea,
(1-8) 1-(adamant-1-yl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
(1-174) 1-(2,4-difluorophenyl)-3-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]urea,
(1-223) 1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
(1-284) 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea,
(1-316) N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)methanesulfonamide,
(2-9) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
(2-24) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
(2-26) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
(2-29) 1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
(6-1) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
(6-7) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]cyclopentanecarboxylic acid amide,
(6-10) N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-19) 2,4-difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
(6-36) N-[4-[2-[4-(2,4dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
(6-37) N-[4-[2-[4-(2,4dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]isonicotinamide, and
(6-59) N-[2-[4-[2-[4-(2,4dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]nicotinamide,
or pharmacologically acceptable salts thereof.
The compound of the formula (I) of the present invention can be prepared according to the following processes. 
In the above formulae, R2, R3, W1, W2, W3, X, Y, Q, Z, Ar and L have the same meanings as defined above, R4 represents a group selected from the substituents a included in the definition of the group R1, and T represents an oxygen atom or a sulfur atom.
Process A is a process for preparing a compound of formula (Ia) in which R1 represents a carbamoyl group or a thiocarbamoyl group which may be substituted in the compound of formula (I).
Step A1 is a step for preparing a compound of formula (Ia) and is carried out by reacting a compound of formula (II) with an isocyanic acid or isothiocyanic acid of formula (III) in the presence or absence of a base in an inert solvent.
The solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; amides such as N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of the above solvents, preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an amide or a mixture of the above solvents (more preferably an aromatic hydrocarbon, an ether or an amide, particularly preferably toluene, tetrahydrofuran or N,N-dimethylformamide).
The base employable in the above reaction is not particularly limited so long as it does not affect the reaction and may preferably include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and ammonia solutions such as aqueous ammonia and concentrated ammonia in methanol.
The reaction temperature varies depending on the starting material, the solvent, etc., but it is usually from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time varies depending on the starting material, the solvent, the reaction temperature, etc., but it is usually from 30 minutes to 5 days (preferably from 5 hours to 72 hours).
After the reaction, the desired compound of formula (Ia) of the present reaction is collected from the reaction mixture according to a conventional method. For example, in the case where the desired compound of formula (Ia) is an insoluble precipitate, the compound is obtained by collecting by filtration and washing with a solvent. In cases other than the above, the compound is obtained by adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R2, R3, W1, W2, W3, X, Y, Q, Z, Ar and L have the same meanings as defined above, R5 and R6 each represent a group selected from the substituents xcex1 included in the definition of the group R1, and W represents an alkoxy group, a nitrogen-substituted imidazole group or a p-nitrophenyloxy group.
Process B is a process for preparing a compound of formula (Ib) in which R1 represents a carbamoyl group which may be substituted in the compound of formula (I).
Step B1 is a step for preparing a compound of formula (Ib) and is carried out by reacting a compound of formula (II) with a compound of formula (IV) in the presence or absence of a base in an inert solvent.
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; amides such as N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of the above solvents, preferably an amide (particularly preferably N,N-dimethylformamide).
The base employable in the above reaction may include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N-N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preferably an organic amine (particularly preferably triethylamine).
The reaction temperature varies depending on the starting material, the solvent, etc., but it is usually from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time varies depending on the starting material, the solvent, the reaction temperature, etc., but it is usually from 30 minutes to 5 days (preferably from 5 hours to 72 hours).
After the reaction, the desired compound of formula (Ib) of the present reaction is collected from the reaction mixture according to a conventional method. For example, in the case where the desired compound of formula (Ib) is an insoluble precipitate, the compound is obtained by appropriately neutralizing the reaction mixture, collecting by filtration and washing with a solvent. In other cases than the above, the compound is obtained by adding the organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant.
The compound of formula (IV) can be obtained by reacting chlorocarbonates or 1,1xe2x80x2-carbonyldiimidazole with amines.
The compound of formula (II) is very useful as a synthetic intermediate of a compound including the compound of the present invention and having an insulin tolerance ameliorating effect, a blood sugar-lowering effect, etc. or a compound having other effects. Preferably, the compound of formula (II) is a compound of the following formula (IIxe2x80x2); more preferably, a compound of the following formula (IIxe2x80x3). 
In the above formulae, R3, W1, W2, W3, X, Y, Q, Z, Ar and L have the same meanings as defined above. 
In the above formulae, R2, R3, W1, W2, W3, X, Y, Q, Z, Ar and L have the same meanings as defined above and R7 represents a group selected from the substituents xcex1 included in the definition of the group R1.
Process C is a process for preparing a compound of formula (Ic) in which R1 is a substituted sulfonyl group in the compound of formula (I).
Step C1 is a step for preparing a compound of the formula (Ic) and is carried out by reacting the compound of formula (II) with a sulfonyl chloride having the formula (V) in the presence or absence of a base in an inert solvent.
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; amides such as N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of the above solvents, preferably an amide (particularly preferably N,N-dimethylformamide).
The base employable in the above reaction may include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an organic amine (particularly preferably triethylamine).
The reaction temperature varies depending on the starting material, the solvent, etc., but it is usually from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time varies depending on the starting material, the solvent, the reaction temperature, etc., but it is usually from 30 minutes to 5 days (preferably from 5 hours to 72 hours).
After the reaction, the desired compound (Ic) of the present reaction is collected from the reaction mixture according to a conventional method. For example, in the case where the desired compound of formula (Ic) is an insoluble precipitate, the compound of formula (Ic) is obtained by appropriately neutralizing the reaction mixture, collecting by filtration and washing with a solvent. In cases other than the above, the compound is obtained by adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R2, R3, W1, W2, W3, X, Y, Q, Z, Ar, L and R7 have the same meanings as defined above.
Process Cxe2x80x2 is a process for preparing a compound of formula (Icxe2x80x2) in which R1is a substituted carbonyl group in the compound of formula (I). Step Cxe2x80x21, which is a step for preparing a compound of the formula (Icxe2x80x2), is carried out by reacting the compound of formula (II) with a compound of formula (Vxe2x80x2) in an inert solvent (a) in the presence of a base according to (b) an active ester method or (c) a mixed acid anhydride method.
(a)
In the case where the compound of formula (Vxe2x80x2) is an acid chloride or an acid anhydride, (a) is a reaction for condensing the compound of formula (II) and the compound of formula (Vxe2x80x2) in the presence of a base.
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; amides such as N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and a mixture of the above solvents; preferably an amides (particularly preferably N,N-dimethylformamide).
The base employable in the above reaction may include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably organic amines (particularly preferably triethylamine).
The reaction temperature varies depending on the starting material, the solvent, etc., but it is usually from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time varies depending on the starting material, the solvent, the reaction temperature, etc., but it is usually from 30 minutes to 5 days (preferably from 5 hours to 72 hours).
(b) Active Ester Method
The active ester method is carried out by reacting the compound of formula (II) with the compound of formula (Vxe2x80x2) in the presence or absence (preferably in the presence) of a condensing agent and a base in an inert solvent.
The active esterifyng agent is preferably used in the presence of a condensing agent, which may include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbornen-2,3-dicarboximide; disulfide compounds such as dipyridyldisulfide; carbodiimides such as 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl)carbodiimide and dicyclohexylcarbodiimide; carbonyldiimidazole; or triphenylphosphine.
The inert solvent employable in the present reaction may include similar inert solvents to those used in the above reaction (a).
The base employable in the present reaction may include the similar bases to those used in the above reaction (a).
The reaction temperature in the active esterification method varies depending on the starting material, the reagent, etc., but it is usually from xe2x88x9270xc2x0 C. to 150xc2x0 C. (preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C.).
The reaction time varies depending on the starting material, the reagent, the reaction temperature, etc., but it is usually from 30 minutes to 80 hours (preferably from 1 hour to 48 hours).
(c) Mixed Acid Anhydride Method
In the case where the compound of formula (Vxe2x80x2) is a carboxylic acid, this method is carried out by preparing a mixed acid anhydride by reacting the compound of formula (Vxe2x80x2) with an agent for forming a mixed acid anhydride in the presence or absence (preferably in the presence) of a base in an inert solvent, and then reacting the mixed acid anhydride with the compound of formula (II) in an inert solvent.
The reagent for forming a mixed acid anhydride employable in the present reaction may include C1-C4 alkyl halocarbonates such as ethyl chloroformate, ethyl chlorocarbonate and isobutyl chlorocarbonate; C1-C5 alkanoyl halides such as pivaloyl chloride; di-(C1-C4 alkyl) or di-(C6-C14 aryl)cyanophosphonic acid derivatives such as diethyl cyanophosphonate and diphenyl cyanophosphonate, preferably a di-(C1-C4 alkyl) or di-(C6-C14 aryl)cyanophosphonate (particularly preferably diethyl cyanophosphonate).
The inert solvent and the base employable in the present reaction are not particularly limited so long as they do not inhibit the reaction and the inert solvent dissolves the starting material to some extent and may include similar inert solvents and bases to those used in the above reaction (a).
The reaction temperature varies depending on the starting material, the reagent, etc., but it is usually from xe2x88x9250xc2x0 C. to 100xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time varies depending on the starting material, the reagent, the reaction temperature, etc., but it is usually from 30 minutes to 72 hours (preferably from 1 hour to 24 hours).
In Process Cxe2x80x2, after the reaction, the desired compound of formula (Icxe2x80x2) of the present reaction is collected from the reaction mixture according to a conventional method. For example, in the case where the desired compound of formula (Ic) is an insoluble precipitate, the compound of formula (Ic) is obtained by appropriately neutralizing the reaction mixture, collecting by filtration and washing with a solvent. In other cases than the above, the compound is obtained by adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R2, R3, W1, W2, W3, X, Y, Q, Z, Ar and L have the same meanings as defined above and Boc represents a t-butoxycarbonyl group.
Process D is a process for preparing the compound of formula (II).
Step D1 is a step for preparing a compound of formula (VIII) and is carried out by reacting a reactive derivative (an acid halide, active ester or mixed acid anhydride) of the compound of formula (VII) with the compound of formula (VI) in an inert solvent.
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane; and a mixture of the above solvents, preferably an ether (particularly preferably tetrahydrofuran).
(a) Acid Halide Method
The acid halide method is carried out by preparing an acid halide by reacting the compound of formula (VII) with a halogenating agent (for example: thionyl chloride, thionyl bromide, oxalic chloride, oxalic dichloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride) in an inert solvent and reacting the acid halide with the compound of formula (VI) in the presence or absence (preferably in the presence) of the base in an inert solvent.
The base employable in the above reaction may include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an organic amine (particularly preferably triethylamine).
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; ketones such as acetone; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane, preferably a halogenated hydrocarbon, an ether or an amide (particularly preferably dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide).
The reaction temperature varies depending on the starting material, the reagent, etc., but it is usually from xe2x88x9220xc2x0 C. to 150xc2x0 C. in both the reaction of the halogenating agent with the compound of formula (VII) and the acid halide with the compound of formula (VI), and is preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C. in the reaction of the halogenating agent with the compound of formula (VII) and from xe2x88x9220xc2x0 C. to 100xc2x0 C. in the reaction of the acid halide with the compound of formula (VI).
The reaction time varies depending on the starting material, the reagent, the reaction temperature, etc., but it is usually from 30 minutes to 80 hours (preferably from 1 hour to 48 hours) in both the reaction of the halogenating agent with the compound of formula (VII) and of the acid halide with the compound of formula (VI).
(b) Active Ester Method
The active ester method is carried out by preparing an active ester by reacting the compound of formula (VII) with an active esterifying agent in an inert solvent and reacting the active ester with the compound of formula (VI) in the presence or absence (preferably in the presence) of a base in an inert solvent.
The active esterifying agent is preferably used in the presence of a condensing agent, which may include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide; disulfide compounds such as dipyridyldisulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; and triphenylphosphine.
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; ketones such as acetone; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane, preferably an ether or an amide (particularly preferably dioxane, tetrahydrofuran or N,N-dimethylformamide).
The base employable in the above reaction may include similar bases to those used in the above acid halide method.
The reaction temperature varies depending on the starting material, the reagent, etc., but it is usually from xe2x88x9270xc2x0 C. to 150xc2x0 C. (preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C.) in the active esterification reaction and from xe2x88x9220xc2x0 C. to 100xc2x0 C. (preferably from 0xc2x0 C. to 50xc2x0 C.) in the reaction of the active ester with the compound of formula (VI).
The reaction time varies depending on the starting material, the reagent, the reaction temperature, etc., but it is usually from 30 minutes to 80 hours (preferably from 1 hour to 48 hours) in both the active esterification reaction and the reaction of the active ester with the compound of formula (VI).
(c) Mixed Acid Anhydride Method
The mixed acid anhydride method is carried out by preparing a mixed acid anhydride by reacting the compound of formula (VII) with an agent for forming a mixed acid anhydride in the presence or absence (preferably in the presence) of a base in an inert solvent and reacting the mixed acid anhydride with the compound of formula (VI) in an inert solvent.
The base employable in the above reaction may include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an organic amine (particularly preferably triethylamine).
The mixed acid anhydride agent employable in the above reaction may include C1-C4 alkyl halocarbonates such as ethyl chlorocarbonate and isobutyl chlorocarbonate; C1-C5 alkanoyl halides such as pivaloyl chloride; di(C1-C4 alkyl) or di(C6-C14 aryl)cyanophosphonic acid derivatives such as diethyl cyanophosphonate and diphenyl cyanophosphonate, preferably a di(C1-C4 alkyl) or di(C6-C14 aryl)cyanophosphoric acid derivative (particularly preferably diethyl cyanophosphonate).
The inert solvent employable in the case of preparing the mixed acid anhydride is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some extent and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether, ketones such as acetone; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane, preferably an ether or an amide (particularly preferably tetrahydrofuran or N,N-dimethylformamide).
The reaction temperature in the reaction for preparing the mixed acid anhydride varies depending on the starting material, the reagent, etc., but it is usually from xe2x88x9250xc2x0 C. to 100xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time in the reaction for preparing the mixed acid anhydride varies depending on the starting material, the reagent, the reaction temperature, etc., but it is usually from 30 minutes to 72 hours (preferably from 1 hour to 24 hours).
The reaction of the mixed acid anhydride and the compound of formula (VI) is carried out in the presence or absence (preferably in the presence) of a base in an inert solvent. The base and the inert solvent employable here are similar to those used in the reaction for preparing the mixed acid anhydride described above.
The reaction temperature in the reaction of the mixed acid anhydride with the compound of formula (VI) varies depending on the starting material, the reagent, etc., but it is usually from xe2x88x9230xc2x0 C. to 100xc2x0 C. (preferably from 0xc2x0 C. to 80xc2x0 C.).
The reaction time in the reaction of the mixed acid anhydride and the compound of formula (VI) varies depending on the starting material, the reagent, the reaction temperature, etc., but it is usually from 5 minutes to 24 hours (preferably from 30 minutes to 16 hours).
In the present reaction, in the case where a di(C1-C4 alkyl)cyanophosphoric acid derivative or di(C6-C14 aryl)cyanophosphoric acid derivative is used, the compound of formula (VI) and the compound of formula (VII) can be directly reacted in the presence of a base.
After the reaction, the desired compound of formula (VIII) of the present reaction is collected from the reaction mixture according to a conventional method. For example, the compound of formula (VIII) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant.
Step D2 is a step for preparing the compound of formula (II) and is carried out by reacting the compound of formula (VIII) with an acid in the presence or absence of an inert solvent.
The acid employable in the above reaction is not particularly limited so long as it is used in a usual reaction as an acid catalyst and may include a Brxc3x8nsted acid such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; an organic acid, e.g., acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; or a Lewis acid such as zinc chloride, tin tetrachloride, boron trichloride or bromine trichloride; or an acidic ion exchange resin, preferably an inorganic acid or an organic acid (particularly preferably hydrochloric acid, acetic acid or trifluoroacetic acid).
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerine, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; or a mixture of water and the above solvents, preferably a halogenated hydrocarbon, an ether, an alcohol or water (particularly preferably dichloromethane, 1,4-dioxane, ethanol or water).
The reaction temperature varies depending on the starting material, the acid used, the solvent, etc., but it is usually from xe2x88x9220xc2x0 C. to the boiling point of the solvent (preferably from 0xc2x0 C. to 50xc2x0 C.).
The reaction time varies depending on the starting material, the acid used, the solvent, the reaction temperature, etc., but it is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).
After the reaction, the desired compound of formula (II) of the present reaction is collected from the reaction mixture according to a conventional method. For example, the compound of formula (II) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous sodium sulfate and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R2, R3, W1, W2, X, Z, Ar, L and Boc have the same meanings as defined above.
Process E is a process for preparing the compound of formula (VI).
Step E1 is a step for preparing the compound of formula (VI) and is carried out by reducing a compound of formula (IX). The present reaction is carried out in an inert solvent using a catalytic reduction reaction or the general method for reduction of a nitro group, i.e., a zinc-acetic acid method, a tin-alcohol method or a tin-hydrochloric acid method, or using sodium dithionite as a reducing agent.
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerine, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water, or a mixed solvent of water and/or any of the above solvents; preferably a halogenated hydrocarbon, an ether, an alcohol or water (particularly preferably dichloromethane, 1,4-dioxane, ethanol or water).
The reaction temperature varies depending on the starting material, the acid used, the solvent, etc., but it is usually from xe2x88x9220xc2x0 C. to the boiling point of the solvent (preferably from 0xc2x0 C. to 50xc2x0 C.).
The reaction time varies depending on the starting material, the acid used, the solvent, the reaction temperature, etc., but it is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).
After the reaction, the desired compound of formula (VI) of the present reaction is collected from the reaction mixture according to a conventional method. For example, in the case of the catalytic reduction reaction, the compound of formula (VI) is obtained by removing the catalyst by filtration from the reaction mixture and distilling off the solvent. In the cases other than the above, the compound of formula (VI) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by a conventional method in appropriate combination, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R2, R3, W1, W2, X, Z, Ar, L and Boc have the same meanings as defined above and Hal represents a halogen atom.
Process F is a process for preparing the compound of formula (IX).
Step F1 is a step for preparing the compound of formula (IX) and is carried out by reacting a compound of formula (X) with a compound of formula (XI) in the presence of a base in an inert solvent.
The base employable in the above reaction may include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an alkali metal hydride (particularly preferably sodium hydride).
The inert solvent employable in the above reaction is not particularly limited so long as it is inactive in the present reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; amides such as N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and a mixture of the above solvents, preferably amide (particularly preferably N,N-dimethylformamide).
The reaction temperature varies depending on the starting material, the base used, the solvent, etc., but it is usually from xe2x88x9250xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 120xc2x0 C.).
The reaction time varies depending on the starting material, the base, the solvent, the reaction temperature employed, etc., but it is usually from 30 minutes to 24 hours (preferably from 1 hour to 10 hours).
After the reaction, the desired compound of formula (IX) of the present reaction is collected from the reaction mixture according to a conventional method. For example, the compound of formula (IX) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by appropriately combining a conventional method, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R3, W2, W3, X, Y, Q, Z, Ar and L have the same meanings as defined above.
Process G is a process for preparing the compound of formula (IIa) in the compound of formula (II) in which W1 is a single bond and both R1 and R2 are hydrogen atoms different from Process D.
Step G1 is a step for preparing a compound of formula (IIa) and is carried out by reducing a compound of formula (XII). The present step is carried out in a similar manner to the above Step E1.
After the reaction, the desired compound of formula (IIa) of the present reaction is collected from the reaction mixture according to a conventional method. For example, after catalytic reduction, the compound of formula (IIa) is obtained by removing the catalyst by filtration from the reaction mixture and distilling off the solvent. In the cases other than the above, the compound of formula (IIa) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by appropriately combining a conventional method, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R3, W2, W3, X, Y, Q, Z, Ar, L and Hal have the same meanings as defined above.
Process H is a process for preparing the compound of formula (XII).
Step H1 is a step for preparing the compound of formula (XII) and is carried out by reacting a compound of formula (XIII) with a compound of formula (XIV) in the presence of a base in an inert solvent. This step is carried out in a similar manner to the above Step F1.
After the reaction, the desired compound of formula (XII) of the present reaction is collected from the reaction mixture according to a conventional method. For example, the compound of formula (XII) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating an organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by appropriately combining a conventional method, for example, a method usually used for separation and a purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant. 
In the above formulae, R3, W2, W3, X, Z, Ar, L and Hal have the same meanings as defined above.
Process I is a process for preparing a compound of formula (XIII).
Step I1 is a step for preparing the compound of formula (XVII) and is carried out by reacting a compound of formula (XV) with a compound of formula (XVI) in the presence or absence of an inert solvent in the presence or absence of a base.
The inert solvent employable in the reaction between the compound of formula (XV) and the compound of formula (XVI) is not particularly limited so long as it is inactive in the reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerine, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; organic acids such as acetic acid and propionic acid; sulfoxides such as dimethyl sulfoxide; and sulfolane; and a mixture of the above solvents.
The temperature for the reaction between the compound of formula (XV) and the compound of formula (XVI) varies depending on the starting material, the base, the solvent used, etc., but it is usually from 0xc2x0 C. to 200xc2x0 C. (preferably from 50xc2x0 C. to 150xc2x0 C.).
The time for the reaction between the compound of formula (XV) and the compound of formula (XVI) varies depending on the starting material, the base, the solvent, the reaction temperature employed, etc., but it is usually from 1 hour to 50 hours (preferably from 5 hours to 24 hours).
After the reaction, the desired compound of formula (XVII) is collected from the reaction mixture according to a conventional method. For example, the compound of formula (XVII) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding the organic solvent immiscible with water such as ethyl acetate, separating an organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by appropriately combining a conventional method, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant.
Step I2 is a step for preparing the compound of formula (XVIII) and is carried out by reacting a compound of formula (XVII) with a halogenating agent (for example, thionyl chloride, thionyl bromide, oxalic chloride, oxalic dichloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.) in the presence or absence of an inert solvent.
The inert solvent employable for the reaction between the compound of formula (XVII) and the halogenating agent is not particularly limited so long as it is inactive in the reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; and a mixture of the above solvents.
The temperature for the reaction between the compound of formula (XVII) and the halogenating agent varies depending on the starting material, the solvent used, etc., but it is usually from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C.).
The time for the reaction between the compound of formula (XVII) and the halogenating agent varies depending on the starting material compound, the solvent, the reaction temperature employed, etc., but it is usually from 30 minutes to 80 hours (preferably from 1 hour to 48 hours).
After the reaction, the desired compound of formula (XVIII) of the present reaction is collected from the reaction mixture according to a conventional method. For example, the compound of formula (XVIII) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by appropriately combining a conventional method, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant.
Step I3 is a step for preparing a compound of formula (XIX) and is carried out by reacting a compound of formula (XVIII) with a nitrating agent (for example, mixed acid, nitric acid, nitronium tetrafluoroborate etc.) in the presence or absence of an inert solvent.
The inert solvent employable for the reaction between the compound of formula (XVIII) and the nitrating agent is not particularly limited so long as it is inactive in the reaction and may include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerine, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; organic acids such as acetic and and propionic acid; sulfoxides such as dimethyl sulfoxide; sulfolane; acetonitrile; and a mixture of the above solvents.
The temperature for the reaction between the compound of formula (XVIII) and the nitrating agent varies depending on the starting material, the solvent used, etc., but it is usually from xe2x88x9220xc2x0 C. to 100xc2x0 C. (preferably from xe2x88x9210xc2x0 C. to 50xc2x0 C.).
The time for the reaction between the compound of formula (XVIII) and the nitrating agent varies depending on the starting material, the solvent used, the reaction temperature, etc., but it is usually from 15 minutes to 48 hours (preferably from 30 minutes to 24 hours).
After the reaction, the desired compound of formula (XIX) of the present reaction is collected from the reaction mixture according to a conventional method. For example, the compound of formula (XIX) is obtained by appropriately neutralizing the reaction mixture, removing insolubles by filtration in the case where insoluble substances are present, adding an organic solvent immiscible with water such as ethyl acetate, separating an organic layer containing the desired compound, washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc. and distilling off the solvent. The desired compound thus obtained can be separated and purified, if necessary, by appropriately combining a conventional method, for example, a method usually used for separation and purification of organic compounds such as recrystallization, reprecipitation, etc., or chromatography using an appropriate eluant.
The compounds of the formula (I) and their pharmacologically acceptable salts of the present invention have superior PPAR xcex3-activation effects, insulin tolerance ameliorating effects, blood sugar lowering effects, anti-inflammatory effects, immunoregulatory effects, aldose reductase inhibitory effects, 5-lipoxygenase inhibitory effects, lipid peroxide formation inhibitory effects, PPAR activation effects, antiosteoporosis effects, leukotriene antagonistic effects, fat cell promotion effects, cancer cell proliferation inhibitor effects and calcium antagonistic effects. The present invention provides treatment and/or prophylaxis for diseases such as diabetes, hyperlipemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (including retinopathy, nephropathy, neuropathy, cataracts and coronary diseases), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (such as ischemic heart diseases), cell injury induced by non-atherosclerotic or ischemic heart disease (such as brain injury induced by stroke), gout, inflammatory diseases (including arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis), cancer, osteoporosis and cataracts by administering to an animal (including a human) in need thereof, an effective amount of a compound of the formula (I).
Moreover, pharmaceutical compositions comprising a combination of the compound of the above formula (I) or their pharmacologically acceptable salts of the present invention and at least one kind of RXR activator (RXR agonist), xcex1-glucosidase inhibitory agent, aldose reductase inhibitory agent, biguanide drug, statin compound, squalene synthesis inhibitory agent, fibrate compound, LDL disassimilation promoter, angiotensin converting enzyme inhibitory agent and FBPase inhibitory agent (particularly preferable are compositions for prevention and/or treatment of diabetes or diabetic complications), are also useful.
The compounds of the formula (I) according to the present invention or pharmacologically acceptable salts thereof can be used for treatment or prevention of the above-described diseases by administering the compound alone or in combination with a suitable pharmacologically acceptable carrier in a suitable dosage form, such as tablets, capsules, granules, powders or syrups for oral administration, or injections or suppositories for parenteral administration. Other usage dosage forms, e.g., ointments and sprays, may be used for alternate administration routes.
These preparations are prepared by a well-known method using carriers such as excipients (which may include organic excipients such as sugar derivatives, e.g., lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives, e.g., corn starch, potato starch, xcex1-starch and dextrin; cellulose derivatives, e.g., crystalline cellulose; gum arabic; dextran; and pullulan; and inorganic excipients such as silicate derivatives, e.g., light silicic anhydride, synthetic aluminum silicate, calcium silicate and magnesium aluminate meta-silicate; phosphates, e.g., calcium hydrogenphosphate; carbonates, e.g., calcium carbonate; and sulfates, e.g., calcium sulfate), lubricants (for example, stearic acid, stearic acid metal salts such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee gum and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leusine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives), binders (for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Macrogol (trade mark) and compounds similar to the above excipients), disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose and internally bridged sodium carboxymethyl cellulose; and chemically modified starch/cellulose such as carboxymethyl starch, sodium carboxymethyl starch and bridged polyvinylpyrrolidone), stabilizers (which may include para-oxy benzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), corrigents (which may include sweeteners, souring agents, flavors, etc. usually used), diluents, etc.
The dose will vary depending on the disease state, age of the patient, e.g. human, the chosen route of administration, etc. In the case of oral administration, a desirable single unit dose contains the compound of the present invention in an amount of 0.001 to 500 mg/kg of body weight and preferably from 0.01 to 50 mg/kg of body weight. In the case of intravenous administration, a desirable single unit dose contains the compound of the present invention in an amount of 0.005 to 50 mg/kg of body weight and preferably 0.05 to 5 mg/kg of body weight. It is desirable to administer the single unit dose one time or several times throughout the day depending on the conditions of the patient. Other dosage forms for other administration routes will also be within the aforesaid ranges and preferably in an amount of 0.01 to 50 mg/kg of body weight. Dosage for treatment or prevention of a specific patient in need thereof is determined by those skilled in the art by applying usual techniques.
The following Examples, Reference Examples and Test Examples are intended to further illustrate the present invention and are not intended to limit the scope of this invention.